Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FKBP (FK506 Binding Protein)

  • Paolo D’Arrigo
  • Martina Tufano
  • Anna Rea
  • Simona Romano
  • Maria Fiammetta Romano
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101769

Synonyms

Synonyms for each gene and encoded protein are listed in Table 1.
FKBP (FK506 Binding Protein), Table 1

FKBP classification with synonyms of gene and protein

GENE

PROTEIN

Name

Other names

Name

Other names

MW (kDa)

FKBP1B

OTK4; FKBP1L; PKBP1L; PPIase; FKBP12.6

FKBP1B

FKBP12.6; calstabin 2; rotamase

11,782

FKBP1A

FKBP1; PKC12; PKCI2; FKBP12; PPIASE

FKBP1A

FKBP12; FKBP1; FKBP12-Exip3; calstabin 1; PKC inhibitor 2; rotamase

11,951

FKBP2

PPIase; FKBP-13

FKBP2

FKBP13; FKBP15.6; proline isomerase; rotamase; rapamycin-binding protein

15,649

FKBP11

FKBP19

FKBP11

FKBP19; rotamase

22,18

FKBP14

EDSKMH; FKBP22; IPBP12

FKBP14

FKBP22; rotamase

24,172

FKBP3

FKBP-3; FKBP25; PPIase; FKBP-25

FKBP3

FKBP25; rapamycin-binding protein; rotamase; rapamycin-selective 25 kDa immunophilin

25,177

FKBP7

FKBP23; PPIase

FKBP7

FKBP23; FKBP30; rotamase

30,009

FKBP6

FKBP36

FKBP6

FKBP36; inactive PPIase FKBP6; rotamase

37,214

AIP

ARA9; XAP2; XAP-2; FKBP16; FKBP37; SMTPHN

AIP

FKBP37; XAP3; HBVX-associated protein 2; immunophilin homolog ARA9, FKBP16

37,636

FKBL

NG7; DIR1;FKBP4;WISP39

FKBL

WISp39; DIR1; Wisp1; FKBPLWAF-1; PPIase; CIP1 stabilizing protein39

38,39

AIPL1

LCA4; AIPL2

AIPL1

Aryl hydrocarbon receptor interacting protein-like1

43,903

FKBP8

FBKP38; FKBPr38

FKBP8

FKBP38; FKBPR8; rotamase

44,562

FKBP5

P54; AIG6; FKBP51; FKBP54; PPIase; Ptg-10

FKBP5

FKBP51; FKBP54; FF1 antigen; androgen-regulated protein 6; progesterone receptor-associated immunophilin; T-cell FKBP; rotamase; HSP90-binding immunophilin

51,212

FBKP4

HBI; p52; Hsp56; FKBP51; FKBP52; FKBP59; PPIase

FKBP4

FKBP52; FKBP59; p59; HSP-binding immunophilin; T-cell FKBP; PPIase; rotamase

51,804

FKBP9

FKBP60; FKBP63; PPIase

FKBP9

FKBP63; rotamase

63,804

FKBP10

OI6; OI11; BRKS1; FKBP65; PPIASE; hFKBP65

FKBP10

FKBP65; rotamase

64,245

FKBP15

FKBP133; PPP1R76; KIAA0674

FKBP15

FKBP135; FKBP15; FKBP133; KIAA0674; FKBP15WAFL; WASP; FKBP-like protein; protein phosphatase 1; regulatory subunit 76

133,63

Historical Background

In the 1970s, after a decade from the purification of cyclosporine, a selective immunosuppressant agent and potent tool in transplantation medicine, a novel molecule was purified from bacteria Streptomyces tsukubaensis. This molecule, called FK506, showed the same selective immunosuppressant action as cyclosporine but was 10- to 100-fold more potent (Kino et al. 1987).

In an attempt to clarify the molecular mechanism through which the new drug exerted such a selective effect on T-cell activation, two laboratories identified the cytosolic receptor for FK506. This so-called FK506 binding protein (FKBP) was purified from bovine thymus, human spleen, and Jurkat T-cell line. The isolated FKBP had an approximate molecular mass of 14 kDa and showed an isomerase activity similar to the recently purified cyclosporine-binding protein, cyclophilin, but it was inhibited by FK506 and rapamycin but not cyclosporine (Siekierka et al. 1989; Harding et al. 1989). The subsequent cloning of FKBP gene revealed that FKBP and cyclophilin had dissimilar sequences in spite of their common enzymatic activity. The identified FKBP gene encoded for a protein of 108 amino acids with a relative molecular mass of 11,819. For this reason, the progenitor of this nascent class of proteins was later known as FKBP12 (Standaert et al. 1990).

The subsequent studies showed that FKBP12 was just a member of a ubiquitous and evolutionarily conserved subfamily of proteins which differ from each other in their molecular weight and structure. All FKBPs share a highly conserved domain, termed “FK-12-like domain,” capable of binding to FK506 and exerting isomerase properties, i.e., interconversion from cis to trans and trans to cis of peptide bonds involving proline, on protein substrates (Fischer and Aumüller 2003).

A schematic historical background of the 17 FKBPs so far identified is shown in Table 2. A general overview of FKBP structure, function, and eventually associated disease is given in this entry, with the order of proteins following the chronology of discovery.
FKBP (FK506 Binding Protein), Table 2

Chronology of FKBP discovery

Date of discovery

FKBP

Description

References

1990

FKBP1A

Purified as the main intracellular receptor for FK506. An approximate molecular mass of 14 kDa was esteemed, and an isomerase activity was identified

Standaert et al. 1990

1990

FKBP4

Identified in IM-9 lymphocytes as part of glucocorticoid receptor complex. The protein showed to interact with both heat shock proteins 90 and 70

Sanchez et al. 1990

1991

FKBP2

Identified as a FK506 and rapamycin-binding protein of 13 KDa. Analysis of amino acid sequence revealed homology with highly conserved sequences of FKBP12 and a possible ER retention sequence at C-terminus

Jin et al. 1991

1992

FKBP3

Identified as a FK506 and rapamycin-binding protein of 25 kDa, encoded by a gene isolated through a human hippocampal cDNA library. The sequence analysis showed high homology with FKBP12

Hung and Schreiber 1992

1993

FKBP5

Identified as part of steroid receptor complex. Sequence analysis showed high homology between FKBP4 and FKBP5 as well as with the FKBP members so far discovered

Smith et al. 1993

1994

FKBP1B

Identified in human fetal brain cDNA library. The gene had high homology with FKBP12 and recombinant protein expressed in E. coli showed to have the same peptidyl-prolyl isomerase activity

Arakawa et al. 1994

1994

AIP

Purified as part of aryl hydrocarbon receptor (AhR) complex, associated with an AhR ligand-binding subunit and Hsp90

Chen and Perdew 1994

1995

FKBP8

Isolated as a cDNA encoding for a 38 kDa protein that showed homology with FKBP12 in its N-terminus. The protein had tetratricopeptide repeat motifs (TPR) and leucine zipper domains suggesting the capacity to interact with other proteins

Lam et al. 1995a

1995

FKBP10

Identified in mouse as a gene that shares homology with the members of FKBP family. Protein characterization revealed three FKBP12-like PPIase domains: the protein is capable of isomerase activity inhibited by FK506 and rapamycin

Coss et al. 1995

1998

FKBP6

Identified as a novel gene localized in 7q11.23 region whose deletion caused Williams syndrome

Meng et al. 1998

1998

FKBP7

The gene was identified in mouse heart by homology analysis with FKBP members. Studies on the protein revealed that it was a glycoprotein retained in endoplasmic reticulum and it was the first FKBP that contained a calcium-binding domain

Nakamura et al.1998

1999

FKBPL

Identified in L132 human cervix cell line, the gene showed to be transiently repressed after low doses of radiation exposure and was probably involved in DNA repair. Molecular characterization revealed that the protein had only the TPR domain that was homologous to the C-terminal of large immunophilins

Robson et al. 1999

1999

FKBP9

Identified in mouse and human cDNA libraries, the gene of FKBP9 showed strong homology with FKBP10

Shadidy et al. 1999

2000

AIPL1

The gene was isolated from a genomic 17p13.1 region that was mutated in Leber’s congenital amaurosis retinopathy. The protein has strong similarity with AIP

Sohocki et al. 2000

2006

FKBP15

Characterized as a novel FKBP involved in nervous system development. The protein had two conserved domains: a FKBP-type peptidyl-prolyl cis–trans isomerase domain and a Wiskott–Aldrich syndrome protein (WASP) homology region 1 (WH1)

Nakajima et al. 2006

2006

FKBP11

Identified through a genome-wide analysis of FKBP genes in human. The protein is secreted

Rulten et al. 2006

2008

FKBP14

FKBP14, whose gene was previously isolated, revealed a possible role in glioblastoma resistance to erlotinib treatment

Halatasch et al. 2008

FKBP1A

See Fig. 1.
FKBP (FK506 Binding Protein), Fig. 1

FKBP1A (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions, ENSG00000088832. (Bottom) Encoded protein(s); isoform a: NP_000792.1, NP_463460; isoform b: NP_001186715.1. The canonical isoform of FKBP1A belongs to the simplest group of FKBPs (also including FKBP1B), which is made up of a single FKBP domain with PPIase activity. This domain is known also as PPIase domain, FK506 binding domain (FKBD) or FK domain

FKBP1A, Function

Ryanodine receptors FKBP12 forms a heterocomplex with ryanodine receptor (RyR1) and regulates Ca2+ flux in vesicles from terminal cisternae of sarcoplasmic reticulum of skeletal muscle. The heterocomplex was dissociated by FK506, suggesting that the interaction involved the active site (PPIase) of FKBP12 (Timerman et al. 1993).

Inositol 1,4,5-trisphosphate receptor FKBP12 was also found to be associated with another important Ca2+ release channel of the endoplasmic reticulum, namely, the inositol 3-phosphate receptor (IP3R) in rat cerebellum. Also in this case, FK506 and rapamycin physically disrupt the heterocomplex FKBP12/IP3R (Cameron et al. 1995).

TGF-βReceptor type I (TβR-I) FKBP12 binds, with its PPIase domain, to the cytoplasmic domain of TβR-I and, specifically, in close proximity to the activating phosphorylation sites in the GS domain (glycine-/serine-rich domain) of TβR-I. FKBP12 stabilizes the inactive conformation of TβR-I by capping the TβR-II phosphorylation sites. FKBP12 is thought to protect the cell by preventing the activation of TβR-I in the absence of ligand. FKBP12 apparently functions as a negative regulator of TβR-I endocytosis. Rapamycin specifically enhances internalization of TβR receptor, suggesting that FKBP12 plays a broader role in TβR signaling than simply inhibiting receptor activation by preventing TβR-I phosphorylation (Okadome et al. 1996).

Epidermal growth factor receptor (EGFR) FKBP12 has an inhibitory role on the autophosphorylation of the tyrosine kinase receptor EGFR; FK506 and rapamycin enhance phosphorylation of EGFR (Lopez-Ilasaca et al. 1998).

mTOR FKBP12 is the intracellular receptor for rapamycin, and the resulting complex interacts with the FKBP12-rapamycin-binding (FRB) domain located in the C-terminus of mTOR. Binding of rapamycin/FKBP12 to the FRB domain precludes the binding of mTOR to the regulatory-associated protein of mTOR (Raptor) which, in turn, uncouples mTORC1 from its substrates (e.g., 4E-BPs and S6Ks) (Kim et al. 2002). In contrast to mTORC1, mTORC2 does not bind rapamycin/FKBP12, and this is thought to confer mTORC2 resistance to acute rapamycin treatment. mTORC2 is sensitive, however, to prolonged rapamycin treatment, which interferes with de novo assembly of mTORC2 (Sarbassov et al. 2006).

FKBP1A and Disease

Alzheimer’s disease FKBP12 promotes the aggregation of full-length tau and co-localizes with neurofibrillary tangles in brain samples from patients with Alzheimer’s disease. The aggregation of a peptide derived from tau depended on FKBP12 PPIase activity (Sugata et al. 2009).

Parkinson’s disease The aggregation of α-synuclein may contribute to Parkinson’s disease. FKBP12 has been identified as the most important FKBP member involved in α-synuclein aggregation (Deleersnijder et al. 2011).

Astrocytoma FKBP12 expression is increased in childhood astrocytoma with a pathogenetic role in tumor aggressiveness. The expression profiles of 13 childhood astrocytomas showed that FKBP12 overexpression was associated with increased expression of HIF-2α and EGFR in malignant high-grade astrocytomas (Khatua et al. 2003).

Chronic lymphocytic leukemia In chronic lymphocytic leukemia (CLL), FKBP12 appeared to mediate CLL cells escape from the homeostatic control of TGF-β. FK506 reactivated the TGF-β signal in CLL and induced apoptosis by a mitochondria-dependent pathway in 33 out of 62 patients (Romano et al. 2008).

FKBP4

See Fig. 2.
FKBP (FK506 Binding Protein), Fig. 2

FKBP4 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000004478. (Bottom) Encoded protein(s): isoform 1, NP_002005.1. FKBP52 belongs to the large immunophilin family and consist of two FKBDs followed by additional functional units. FKBP52 contains a tandem FKBD separated by a short linker sequence. The N-terminal FKBD is responsible for the PPIase- and ligand-binding activities. The C-terminal FKBD is inactive in those activities, but seems to retain an interaction ability. This domain contains an ATP-/GTP-binding sequence. For map legend, see Fig. 1

FKBP4, Function

FKBP52 has a conserved threonine residue in the linker loop region, which is the major site of phosphorylation by casein kinase 2 both in vitro and in vivo. The phosphorylation negatively regulates the physiological activity of FKBP52; however, the molecular mechanism of this functional regulation remains unclear (Miyata et al. 1997).

Steroid hormone regulation FKBP52 is well characterized as a positive regulator of steroid hormone receptor, both in vitro and in vivo (Sivils et al. 2011). Deletion or reduction of FKBP52 resulted in reduced steroid hormone signaling. Particularly, FKBP52 acts as a positive regulator of the glucocorticoid receptor (Riggs et al. 2003), progesterone receptor (Tranguch et al. 2005), and estrogen receptor (Cheung-Flynn et al. 2005), but not for the androgen receptor (Sivils et al. 2011). FKBP52 associates with receptor–Hsp90 complexes and is proposed to have roles in both receptor hormone binding and receptor subcellular localization. FKBP52 shares 70% similarity with FKBP51, but these proteins are functionally divergent and compete for binding to the steroid hormone–receptor complex. As a result, overexpression of FKBP51 counteracts receptor regulation by FKBP52 and decreases hormone–receptor function. This diversity is largely attributed to differences in the FK1 domain that may directly contact the receptor ligand-binding domain, in the proline-rich loop. Several FKBP52 functions are mediated through steroid hormone response including a neurotrophic activity, FKBP52 knockdown dramatically reduced neurite outgrowth in N2a neuroblastoma cells. FKBP52 knockout in male mice displays phenotypes consistent with partial androgen insensitivity including dysgenic prostate and seminal vesicles, ambiguous external genitalia including hypospadias, with normal testis development. FKBP52 also regulates sperm motility, an androgen-independent process, due to its interaction with dynein motor proteins (Sivils et al. 2011). FKBP52 and FKBP51 have emerged as potential therapeutic targets for a wide variety of endocrine-related diseases including prostate cancer, breast cancer, male and female contraception, stress-related diseases, and metabolic diseases (Sivils et al. 2011).

Microtubule dynamics FKBP52 binds to tubulin and promotes microtubule depolymerization in vitro; particularly, it binds to the microtubule associated protein tau, especially when tau is phosphorylated. Moreover, FKBP52 binds to dynein, at the PPIase domain, and to glucocorticoid receptor/Hsp90 complex, at its TPR domain, acting as an adaptor protein that favors nuclear migration of steroid hormone–receptor complex (Cioffi et al. 2011).

RNA-induced silencing complex (RISC) assembly FKBP52, together with FKBP51, are endonuclease Ago2-associated proteins in mouse embryonic stem cells, involved in mRNA degradation. Pharmacological inhibition of this interaction using FK506 or siRNA-mediated FKBP4/5 depletion leads to decreased Ago2 protein levels (Martinez et al. 2013).

NF-κB signaling FKBP52 favors the nuclear retention of RelA and its association to a DNA consensus binding sequence. Through this mechanism, the NF-κB transcriptional activity is sustained. Such an effect is strongly dependent on both the peptidyl-prolyl-isomerase activity and the TPR domain of FKBP52 (Erlejman et al. 2014).

Store-operated calcium entry (SOCE) Calcium entry from the extracellular space into cells is an important signaling mechanism in both physiological and pathophysiological functions. In non-excitable cells, SOCE represents a principal mode of calcium entry. FKBP52 and FKBP51 have a regulatory role. In particular, FKBP51 inhibits, whereas FKBP52 enhances, SOCE in endothelial cells and in human platelets (Lopez et al. 2013).

Copper transport FK1 domain of FKBP52 interacts with Atox1, a copper-binding metallochaperone that regulates copper efflux. The interaction between FKBP52 and Atox1 was observed in vitro. The FKBP52/Atox1 interaction was enhanced when HEK 293 T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, suggesting that the interaction is regulated in part by intracellular copper. Through control of copper efflux machinery, FKBP52 promotes neuroprotection from copper toxicity (Sanokawa-Akakura et al. 2004).

Transient receptor potential channels regulation FKBP52 was found to associate with canonical transient receptor potential channels (TRPC1) through PPIase domain; these channels are known to be involved in the chemotrophic guidance of neuronal growth cones via regulation of TRPC1 channel opening (Hausch 2015).

FKBP4 and Disease

Cancer In prostate cancer cell lines and biopsies from human patients, FKBP52 was found overexpressed, together with FKBP51. Compounds that specifically inhibit FKBP52 effectively blocked androgen-dependent gene expression and cell proliferation in prostate cancer cells (Periyasamy et al. 2007). FKBP52 expression is also upregulated in breast tumors and recent studies found FKBP52 gene methylation in estrogen receptor-negative, but not in estrogen receptor-positive breast cancer cells, suggesting that repression of FKBP52 may, itself, affect estrogen receptor expression. FKBP52 FK1 domain and the proline-rich loop within this domain are functionally important for FKBP52 regulation of estrogen receptor (Sivils et al. 2011).

Neuronal disease PPIase activity causes alterations in the processing of Alzheimer’s amyloid precursor protein (APP). The observation that FKBP52 is highly expressed in CNS regions susceptible to Alzheimer’s raised the hypothesis that, due to its enzymatic function, this protein may be involved in β-amyloid toxicity. However, in mammalian cultures, FKBP52−/− cells have increased intracellular copper and higher levels of β-amyloid (Sanokawa-Akakura et al. 2010). FKBP52, as well as other members of the FKBP family, are known to accelerate the aggregation of alpha-SYN in vitro. Knockdown of FKBP52 reduces the number of alpha-SYN aggregates and protects against cell death, whereas overexpression of FKBP52 accelerates both aggregation of alpha-SYN and cell death (Cioffi et al. 2011). RET51 is a proto-oncogene in neurons and its activation by both glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) triggers the formation of a RET51/FKBP52 complex. The substitution of the tyrosine 905 of RET51, a key residue phosphorylated by both GDNF and NGF, disrupts the RET51/FKBP52 complex. NGF and GDNF have a functional role in dopaminergic neurons, where RET51 and FKBP52 are expressed. Mutations in RET and FKBP52 disrupt the RET51/FKBP52 complex and have a potential role in Parkinson disease (Fusco et al. 2010).

FKBP2

See Fig. 3.
FKBP (FK506 Binding Protein), Fig. 3

FKBP2 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000173486. (Bottom) Encoded protein: NP_476433.1, NP_004461.2, NP_001128680.1. This protein belongs to a second group within the FKBP family, which possess one FKBP domain, an additional N-terminal alpha helix and an extra C-terminal amino acids. The N-terminal helix contains a signal peptide responsible for membrane association, while the additional C-terminal amino acids are essential for ER localization. This group of proteins includes the human FKBP2, FKBP11, and FKBP14. For map legend, see Fig. 1

FKBP2, Function

Endothelial reticulum (ER) molecular chaperone FKBP13 plays a role in ER protein folding; sequencing of the 5′ flanking region of murine gene revealed significant similarity with human BiP (immunoglobulin-binding protein) and the human glucose-regulated protein GRP94. Particularly, a 37 bp sequence in FKBP13 has approximately 50% identity with the unfolded protein response element of the BiP gene (Bush et al. 1994).

Vesicular trafficking FKBP13 physically interacts with BIG1, which is a protein involved in vesicular trafficking, and it moves between Golgi membranes and cytosol: yeast two-hybrid screens of a human placenta cDNA library with BIG1 cDNA constructs revealed the specific interaction of its N-terminal region with FKBP13. The association was confirmed by immunoprecipitation of both endogenous BIG1 and FKBP13 in Jurkat T cells. FK506 increased binding of BIG1, BIG2, and ARF to Golgi and other membranes in a time- and concentration-dependent manner, in Jurkat T cells (Bush et al. 1994).

Complement C1q FKBP13 interacts with the C-chain of complement C1q (C1q-C), as suggested by experiments conducted in the yeast two-hybrid system and in a protein complementation assay. The interaction was highly specific. Binding of C1q-C to FKBP13 is not prevented by FK506, demonstrating that regions, other than the binding pocket of the drug, are responsible for the interaction of the two proteins (Neye and Verspohl 2004).

Erythrocyte membrane FKBP13 has been identified also in erythrocytes, which lack ER. FKBP13 interacts, with the erythrocyte membrane cytoskeletal protein 4.1Gs, suggesting that FKBP13 may have an additional function as a component of membrane cytoskeletal scaffolds (Walensky et al. 1998).

FKBP3

See Fig. 4.
FKBP (FK506 Binding Protein), Fig. 4

FKBP3 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000100442. (Bottom) Encoded protein: NP_002004.1. FKBP3 contains just one C-terminal FKBP domain, a central helix-loop-helix (HLH) motif, which is responsible for the binding to nucleic acid. For map legend, see Fig. 1

FKBP3, Function

Chromatin remodeling The nuclear FKBP25 physically associates with the histone deacetylases HDAC1 and HDAC2 and with the HDAC-binding transcriptional regulator YY1. An FKBP25 immunoprecipitated complex contains deacetylase activity, and this activity is associated with the N-terminus of FKBP25, in a region distinct from the FK domain. Furthermore, FKBP25 is also able to alter the DNA-binding activity of YY1 (Yang et al. 2001). FKBP25 is also associated with the core histones of the nucleosome and with several proteins forming spliceosomal complexes. FKBP25 phosphorylation by casein kinase II enhances its nuclear localization and association with nucleolin (Jin and Burakoff 1993). FKBP25 has an intrinsic capacity to form complexes with polyribonucleotides. Through the interaction with different protein partners, FKBP25 regulates packaging of DNA, chromatin remodeling, and pre-mRNA splicing, whereas the cytosolic pool of this immunophilin is bound to some components of the ribosome. FKBP25 interacts with the immature large ribosomal subunit yet in the nucleus, implicating an action in ribosome biogenesis (Gudavicius et al. 2014).

p53 A regulatory loop involving the tumor suppressor gene p53 and FKBP25 has been reported. FKBP25 stimulated auto-ubiquitylation and proteasomal degradation of mouse MDM2 homolog, leading to the induction of p53 and its downstream effector p21 (Ochocka et al. 2009). Conversely, FKBP25 resulted decreased by p53 activation, following DNA damage (Ahn et al. 1999).

FKBP5

See Fig. 5.
FKBP (FK506 Binding Protein), Fig. 5

FKBP5 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000096060. (Bottom) Encoded protein(s): isoform 1, NP_004108.1, NP_001139247, NP_001139248; isoform 2, NP_001139249.1. FKB51 contains a tandem FKBD separated by a short linker sequence. The N-terminal FKBD is responsible for the PPIase- and ligand-binding activities. The second FKBD is inactive in those activities, but seems to retain an interaction ability. This domain contains an ATP-/GTP-binding sequence. For map legend, see Fig. 1

FKBP5, Function

T-cell activation FKBP51 is capable of immunosuppression when complexed to FK506. Such effect is mediated by inhibition of calcineurin (CaN), the Ca2+/calmodulin-dependent serine–threonine phosphatase, that regulates the clonal expansion of T cells after stimulation by an antigen, through activation of the nuclear factors of activated T lymphocytes (NFAT). Among FKBPs, only FKBP12, FKBP12.6, and FKBP51 can mediate FK506 effects on CaN activity in human cells, whereas other FK506/FKBP complexes do not contribute to the inhibition of CaN protein phosphatase activity (Baughman et al. 1995; Hogan et al. 2003).

Steroid receptor regulation In the glucocorticoid receptor, the superchaperone receptor complex facilitate dimerization and nuclear transport of the hormone–receptor complex when it contains FKBP52. In a different way, the FKBP51-containing complexes attenuate the glucocorticoid binding, resulting in attenuation of the glucocorticoid action. Glucocorticoids upregulate the gene for FKBP51, which provides a mechanism for desensitization of cells after an initial exposure to the hormone (Cheung and Smith 2000).

Adipogenesis FKBP51 accumulates during the expansion phase preceding adipocyte differentiation. During this phase, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nuclear matrix. Mitochondrial–nuclear shuttling of FKBP51 depends on protein kinase A signaling. FKBP51 knockdown facilitates the process of adipocyte differentiation, whereas ectopic expression of FKBP51 lowers it (Yeh et al. 1995).

NF-κB activation FKBP51 physically interacts with IKK subunits and facilitates IKK complex assembly. The IKK-regulatory role of FKBP51 involves both its scaffold function and its isomerase activity. Moreover, FKBP51 also interacts with TRAF2, an upstream mediator of IKK activation. Both FKBP51 TPR and PPIase domains are required for its interaction with TRAF2 and IKKγ, whereas only the TPR domain is involved in interactions with IKKα and β (Romano et al. 2015c). FKBP51 sustains NF-κB activation induced by doxorubicin and ionizing radiation (Romano et al. 2004; Romano et al. 2010).

TGF-β signaling FKBP51 participates to transcriptional complexes involving Smad 2/3 and p300 and supports transcription of SLUG, VIM, and CDH2 in melanoma (Romano et al. 2014).

Akt pathway FKBP51 is an essential chaperone to the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase. In pancreatic cell lines, FKBP51 is downregulated and acts as a scaffolding protein for Akt and PHLPP to promote dephosphorylation of Akt. FKBP51 binds PHLPP and Akt using distinct domains (FK1 for PHLPP and TPR for Akt) (Pei et al. 2009).

Programmed death-ligand 1 (PD-L1) The spliced isoform 2 of FKBP51 (FKBP51s) exerts posttranslational control on PD-L1 (or B7 homolog 1 or B7-H1) expression, acting as a foldase of PD-L1 protein in ER and assisting to glycosylation (PCMR) (Romano et al. 2015a).

FKBP5 and Disease

Idiopathic myelofibrosis FKBP51 is overexpressed in idiopathic myelofibrosis, the chronic myeloproliferative disorder characterized by megakaryocyte hyperplasia and bone marrow fibrosis. Overexpression of FKBP51 in this disorder regulated the growth factor independence of megakaryocyte progenitors and promoted fibrosis, mediated by upregulation of TGF-β synthesis (Komura et al. 2005).

Prostate cancer Elevated levels of FKBP51 have been found in human prostate cancer samples. FKBP51 reduces estrogen-, progesterone-, and mineralocorticoid-receptor transcriptional activities, but, in the androgen receptor (AR) superchaperone complexes, FKBP51 increases the amount of hormone-bound receptor, which increases the androgenic signals. More specifically, FKBP51 stimulates recruitment of the co-chaperone p23 to the ATP-bound form of Hsp90, forming an FKBP51–Hsp90–p23 superchaperone complex. FKBP51 promotes superchaperone complex association with AR and increases the number of AR molecules that undergo androgen binding (Ni et al. 2010). Androgens, in turn, cause upregulation of FKBP51 expression through a direct binding of AR to enhancer elements in the FKBP51 gene, creating an autoregulatory pathway designed to increase androgen sensitivity.

Melanoma aberrant expression of FKBP51 in melanoma with a relevant role in chemo- and radioresistance (Romano et al. 2004, Romano et al. 2010). FKBP51 promotes activation of epithelial-to-mesenchymal transition genes and improved melanoma cell migration and invasion (Romano et al. 2013). FKBP51 participates to transcriptional complexes regulating expression of ABCG2 gene and sustains melanoma stemness. FKBP51-targeting prevented melanoma colonization of liver and lungs in a mouse model of experimental metastasis (Romano et al. 2013). Melanoma interaction with immune system through PD-L1/PD1 activates the splicing of FKBP5 and generates the isoform 2, which, in turn, upregulates PD-L1 expression bidirectionally (on both melanoma and immune cells) (Romano et al. 2015a).

Glioma Enhanced FKBP51 expression is associated with apoptosis resistance and enhanced proliferation in gliomas. The FKBP51 expression level correlated with tumor grading (Jiang et al. 2008).

Depression Several studies reported an association between specific FKBP5 gene polymorphisms, recurrence of depressive episodes, and rate of antidepressant response. In some cases, SNPs are correlated with higher FKBP51 protein levels and recurrence of depressive episodes, but also a more rapid response to antidepressant treatment. The mechanism is related to the inhibitory action of FKBP51 on glucocorticoid receptors in central stress response, which is deregulated in the majority of depressed patients (Schmidt et al. 2012). FKBP5−/− mice show antidepressant behavior without affecting cognition and other basic motor functions and produce reduced corticosterone levels upon stress. Moreover, while in wild-type mice, behavioral correlates of anxiety decreased with age, these appeared to increase in FKBP5−/− mice.

Tauopathies FKBP51 showed to have a role in neurodegenerative disorders termed tauopathies, caused by accumulation in the neurons of the tau protein, the most common being Alzheimer’s disease. FKBP51 promotes tau recycling: through association with Hsp90, FKBP51 isomerizes tau to the cis conformation, allowing for dephosphorylation and recycling to the microtubule. Blocking PPIase activity of FKBP51 perpetuates the association of phospho-tau with Hsp90, promoting tau accumulation (Jinwal et al. 2010).

FKBP1B

See Fig. 6.
FKBP (FK506 Binding Protein), Fig. 6

FKBP1B (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000119782. (Bottom) Encoded protein(s); isoform a: NP_004107.1; isoform b: NP_473374.1; isoform c: NP_001309892.1; NP_001309893.1. The canonical isoform of FKBP1B contains a single FKBP domain with PPIase activity. This domain is known also as PPIase domain, FK506 binding domain (FKBD), or FK domain. For map legend, see Fig. 1

FKBP1B, Function

Ryanodine receptors FKBP12.6 differs from FKBP12 in 16 of 107 amino acid residues. This protein binds RyR2 in cardiac muscle sarcoplasmic reticulum (Lam et al. 1995b). The RyR2 channel is a tetrameric complex consisting of four RyR2 subunits, four FKBP12.6, and many other interacting components. Upon phosphorylation by protein kinase A (PKA), FKBP12.6 dissociates from the complex allowing Ca2+ release (Marx et al. 2000).

FKBP1B and Disease

Cardiac disease Dissociation of FKBP12.6 from RyR2 increases the channel open probability and induces subconductance states which may provide substrates for arrhythmia. In heart failure, characterized by chronic activation of the adrenergic system, RyR2 channels are hyperphosphorylated resulting in their depletion of FKBP12.6 which in turn positively regulates the calcium-induced calcium release (CICR) (Lahat et al. 2001). In a dog model of experimental heart failure, oral administration of beta-adrenergic blockers reversed PKA-induced RyR2 phosphorylation, restored the binding of FKBP12.6 to RyR2 and normalized the RyR2 channel function in in vitro lipid bilayers from myocardial strips prepared from patients undergoing heart transplantation (Reiken et al. 2003). By contrast, Jiang et al., studying functional properties of the cardiomyocytic calcium-signaling system from exercise-induced tachycardia canine model as well as human hearts, did not find any evidence for abnormal interaction of phosphorylated RyR2 with FKBP12.6 or RyR2 leakage (Jiang et al. 2002). Catecholaminergic polymorphic ventricular tachycardia is characterized by mutant RyR2 channels, showing a gain-of-function defect. The RyR2 mutant channels are phosphorylated to the same degree as the wild-type channels, but their binding affinity to FKBP12.6 decreased more than that of the wild-type channels (Lehnart et al. 2004).

Diabetes mellitus FKBP12.6 knockout mouse resulted in enhanced glucose-stimulated insulin secretion both in vivo and in vitro, due to enhanced glucose-induced Ca2+ elevation in β-cells of pancreatic Langerhans islets (Chen et al. 2010). By contrast, Noguchi et al. described a glucose intolerance coupled to insufficient insulin secretion upon a glucose challenge in FKBP12.6−/− islets (Noguchi et al. 2008).

AIP

See Fig. 7.
FKBP (FK506 Binding Protein), Fig. 7

AIP. (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000110711. (Bottom) Encoded protein(s): isoform 1, NP_003968.3; isoform 2, NP_001289888.1; isoform 3, NP_001289889.1. AIP has an inactive FKBD domain, followed by TPR domains. For map legend, see Fig. 1

AIP, Function

Aryl hydrocarbon receptor (AHR) AIP shares structural similarity with FKBP52. The FK domain of AIP is unable to exert PPIase activity due to a particular structural feature that covers the active site (Linnert et al. 2013). High levels of expression were observed in the spleen, thymus, and pituitary gland and low expression levels in the liver, kidney, and lung. The N-terminal part of AIP is important for the stability of the ternary AHR–Hsp90–AIP complex and is essential to regulate the intracellular localization of AHR (Kazlauskas et al. 2002). Most of AIP mutations completely disrupt the C-terminal TPR domain, leading to failure of client–protein interaction. AIP retains AHR, not bound to the ligand, in the cytoplasm, thanks to the formation of an inactive complex consisting of a dimer of Hsp90 and a single AIP molecule that binds to the AHR nuclear localization sequence. This inactive complex promotes ubiquitination and proteasomal degradation of AHR (Lees et al. 2003). AIP also regulates the cytoplasmic localization of the AhR, through association with actin or tubulin filaments (Trivellin and Korbonits 2011).

CARD-containing MAGUK protein 1(Carma 1) AIP acts as a positive regulator of the ternary complex CBM (CARMA1, BCL10, and MALT1), through the interaction between the N-terminal PPIase domain of AIP and the C-terminal of CARMA1, stabilizing its active conformation. The CBM complex is essential for the signal transmission from the T-cell receptor (TCR) to the IKK complex for the activation of the NF-κB signaling. AIP downregulation induces a decrease in IKKα/β phosphorylation activity (Schimmack et al. 2014).

Pre-ornithine transcarbamylase (pOTC) AIP binds mitochondrial pre-proteins as pOTC, recognizing and interacting with NH2-presequences of these proteins, but also identifying their internal import signals. This interaction stabilizes pOTC in the cytosol and facilitates its import into mitochondria. In the cytosol, AIP functions as co-chaperone with heat shock chaperone 70, forming a complex with mitochondria-targeted pre-proteins to suppress their aggregation and prevent their degradation until these pre-proteins are transferred to mitochondrial receptor translocase of the outer membrane of mitochondria (Tom20) (Yano et al. 2003).

Interferon regulatory factor 7 (IRF-7) AIP is a binding partner of IRF-7. This interaction is enhanced upon a viral infection and AIP potently inhibits IRF7-induced IFNα/β production (Zhou et al. 2015).

Glucocorticoid receptor (GR) The effect of AIP on the GR signaling is inhibitory due to a delayed nuclear accumulation of GR after ligand binding, with a subsequent decrease of GR’s transcriptional activity. AIP also inhibits the transcriptional activity of the receptors for progesterone and androgen (Schulke et al. 2010).

Estrogen receptor AIP is recruited to the promoter of estrogen receptor-α-regulated genes and negatively modulates the transcriptional activity of the receptor by interacting with the co-activator TIF-2 (transcriptional mediators/intermediary factor 2). AIP action is dependent on the protein–protein interaction of AIP with estrogen receptor-α (but not -β) on the promoter of estrogen receptor-target gene (Cai et al. 2011).

AIP and Disease

Pituitary adenomas Several studies on a different cohort of patients have demonstrated that AIP mutations predispose to familial isolated pituitary adenomas (FIPAs) [23,310,926 20,506,337] and to sporadic pituitary adenomas (Woods et al. 1990) that occur at a young age. A homozygous Aip inactivation is in embryo lethal. Aip−/− embryos die due to cardiovascular defects. Heterozygous Aip mice grew normally but develop multiple pituitary tumors, as early as at 6 months of age. All mice developed pituitary tumors at 15 months (Raitila et al. 2010), unlike human tumors that are not associated with 100% of penetrance (Beckers et al. 2013), because of a different genetic background influence. Moreover, in different cell lines, pituitary tumorigenesis is due to AIP mutations that cause elevated cyclic adenosine monophosphate (cAMP) levels due to a defective Gαi protein signaling. High cAMP level promotes AHR ubiquitination and proteasomal degradation (Nakata et al. 2009).

Hepatitis B AIP is also called Hepatitis B virus X-associated protein2 (XAP2) and specifically binds to the N-terminal of Hepatitis B Virus X-protein, a factor important for transactivation of viral and cellular genes. This interaction inhibits X transactivation by sequestering cellular proteins important for this process (Kuzhandaivelu et al. 1996).

Epstein–Barr virus-induced transformation AIP can in vitro bind to one of the six nuclear antigens of Epstein–Barr virus nuclear antigen 3 (EBNA-3) expressed in an EBV-immortalized lymphoblastoid cell, which is essential for the immortalization and transformation of B cells. EBNA-3 can also directly interact with the AhR, with AIP enhancing the stability of the complex and transcription of AhR-responsive genes. Among these genes, there are those involved in virus-induced cell transformation (Kashuba et al. 2006).

FKBP8

See Fig. 8.
FKBP (FK506 Binding Protein), Fig. 8

FKBP8 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000105701. (Bottom) Encoded protein(s): isoform 1, NP_036313.3; isoform b, NP_001295302.1. FKBP38 contains FKBD (PPIAse inactive), tripartite TPR domain, putative calmodulin (CBD), and transmembrane (TM) motifs. For map legend, see Fig. 1

FKBP8, Function

Calcineurin (CaN) FKBP38 is composed of an N-terminal glutamate-rich region followed by a PPIase domain, three TPR motifs, a CaM-binding site, and a membrane anchor near its C-terminal. This C-terminal is unique among all the FKBPs and is able to target the protein to mitochondrial outer membrane and ER membrane. FKBP38 isomerase activity is inhibited by transient interactions involving the flexible N-terminal and the catalytic domain that covers the active site (Edlich and Lucke 2011). FKBP38 is an FK506-independent CaN inhibitor, suggesting that the inactive PPIase domain of FKBP38 mimics the FKBP12/FK506 complex and inhibits CaN (Shirane and Nakayama 2003). By contrast, according to Weiwad et al., FKBP38 cannot substitute for the FKBP/FK506 complex in signaling pathways controlled by the protein phosphatase activity of calcineurin (Weiwad et al. 2005).

Mammalian target of rapamycin complex 1 (mTORC1) FKBP38 binds and inhibits mTOR in a dose-dependent manner (Yoon et al. 2011). FKBP8 is also antagonized by the Ras homolog enriched in brain (Rheb) in a GTP-dependent manner because GTP-Rheb induces the release of mTOR by the PPIase domain of FKBP8 to promote its own binding to the immunophilin (Bai et al. 2007).

Mitochondria FKBP8 resides in the mitochondrial outer membrane and endoplasmic reticulum (ER) membrane, and its role is to anchor the 26S proteasome to these organelles and regulate protein degradation. Among the proteins that are influenced by this regulation, there is the prolyl-4-hydroxylase domain-containing enzyme (PHD2). FKBP8 interacts through its Glu-rich segment with the N-terminal PHD2, thus increasing PHD2 degradation by the proteasome. This event does not allow the hydroxylation and consequent degradation of HIFα. Moreover, FKBP8 escapes from mitochondria through shuttling from the mitochondrial outer membrane to ER, during mitophagy process. The physiological relevance of FKBP38 translocation during mitophagy is unknown (Saita et al. 2013).

Anti-apoptotic function FKBP38 plays an anti-apoptotic effect targeting Bcl-2 and Bcl-xL to mitochondria, where these proteins inhibit mitochondrial-dependent apoptosis (Shirane and Nakayama 2003).

Pro-apoptotic function During mouse eye development, FKBP8 interaction with Bcl2/Bcl-XL has a pro-apoptotic function, essential for retinal pigment epithelial cells homeostasis. The binding of FKBP8 to Bcl2 can prevent Bcl2 from interacting with BAD and CaN and therefore can prevent the anti-apoptotic functions of Bcl2 (Chen et al. 2008). FKBP38 is a pro-apoptotic regulator also in neuroblastoma cells (Erdmann et al. 2007). FKBP8 is an inactive PPIase which becomes active when Ca2+ intracellular rises, and therefore the immunophilin forms a complex with Ca2+/calmodulin. Only this active complex interacts with Bcl2. In neuronal tissues, such complex promotes conformational changes that disrupt Bcl2 interaction with the pro-apoptotic protein BAD and, by this mechanism, apoptosis is activated (Edlich et al. 2005).

Ion channels FKBP38 associates with nascent plasma membrane ion channels in the endoplasmic reticulum (ER). FKBP38 promotes the processing of the voltage-dependent delayed rectifier potassium channel. It also regulates the cystic fibrosis transmembrane conductance regulator (CFTR) controlling its synthesis and posttranslational folding in vitro by N-terminal glutamate-rich domain. Interestingly, FKBP38 has been found to associate with ion channels in the ER together with Hsp70, Hsp90, Hsp40, Hop, and p23 (Banasavadi-Siddegowda et al. 2011).

Sonic hedgehog pathway FKBP38 plays a role in the neural tube formation, mediated by increase in sonic hedgehog homolog (SHH) levels and signaling (Cho et al. 2008).

FKBP8 and Disease

Hepatitis C There is an interaction between FKBP38 and the hepatitis C virus (HCV) nonstructural protein NS5A, which plays an important role in viral replication, through the TPR domain of FKBP38. Both proteins are localized in the mitochondria and in the endoplasmic reticulum. Their interaction plays an important role in promoting HCV replication and apoptosis evasion of HCV-infected liver cells (Wang et al. 2006).

FKBP10

See Fig. 9.
FKBP (FK506 Binding Protein), Fig. 9

FKBP10. (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000141756. (Bottom) Encoded protein(s): isoform 1, NP_068758.3. FKBP10 has two EF-Hand domains in the C-terminus and four FKBP domains at the N-terminus. For map legend, see Fig. 1

FKBP10, Function

Collagen and tropoelastin synthesis FKBP65 assists in the folding of the proline-rich extracellular matrix proteins collagen and tropoelastin (Ishikawa et al. 2008). FKBP65 interacts with unfolded and folded (triple helical) collagens and, in this regard, seems to resemble HSP47. FKBP65 binds BiP in the endoplasmic reticulum (ER) (Davis et al. 1998). Stress-induced changes, in the ER Ca2+ stores, induce the rapid proteolysis of FKBP65. Ca2+ binding at EF-hand domains might play an important role in regulating the stability of FKBP65 during ER stress (Murphy et al. 2011).

FKBP10 and Disease

Osteogenesis imperfecta Mutations in the FKBP10 gene cause the autosomal recessive osteogenesis imperfect (OI) due to impaired collagen folding. In a patient with OI type XI from Iran, FKBP65 resulted in the deletion of two PPIase domains and two C-terminal EF-hand motifs. EF-hand motifs are calcium ion binding sites that are a necessary for the conformational changes that enable Ca2+-regulated functions. Twenty-three different disease-causing mutations have been identified in the FKBP10 gene, which includes missenses/nonsense (30%), splicing site (4%), small deletions (13%), small insertions (34%), small indels (8%), and gross deletions (8%) (Alanay et al. 2010).

Bruck Syndrome 1 is caused by a homozygous mutation in the FKBP10 gene. Bruck syndrome type 1 patients have under-hydroxylated lysine residues in the collagen telopeptide and, as a result, show diminished hydroxylysylpyridinoline cross-links (Barnes et al. 2012).

Colon adenoma and adenocarcinoma An increased level of FKBP10 was observed in colon adenomas and adenocarcinomas. Normal colon mucosa showed low/no FKBP10 expression. The immunophilin is expressed in very early benign lesions and appears involved in the initiation of colorectal carcinogenesis (Olesen et al. 2005).

Ovarian cancer FKBP10 exerts a tumor suppressor function in the ovary. The strong epithelial expression of FKBP10 in normal ovaries is decreased in ovarian cancer and is associated with a decreased patient survival. An altered collagen function in ovarian cancer is responsible for a decreased resistance to tumor invasion and thus contributes to faster tumor progression. Reduced FKBP10 protein expression is related to the frequent loss of chromosome 17 in epithelial ovarian carcinomas, particularly high-grade serous carcinomas (HGSC) (Henriksen et al. 2011).

Idiopathic pulmonary fibrosis FKBP10 has been suggested to be important for normal lung development. In normal adult tissues, its expression is low and appears to be reactivated during lung fibrosis. FKBP10 is overexpressed in bleomycin-induced lung fibrosis and idiopathic pulmonary fibrosis (Patterson et al. 2005).

Prion disease Targeting of FKBP10 affects prion protein biogenesis at a late stage, improving its disposal by both proteasomal and lysosomal pathways (Stocki et al. 2016).

Leukemia FKBP10 has a role in the acquisition and maintenance of the adriamycin-resistant phenotype in leukemia cells; targeting this gene is able to reverse the drug-resistant phenotype of chronic myelogenous leukemia K562 cells (Sun et al. 2014).

FKBP6

See Fig. 10.
FKBP (FK506 Binding Protein), Fig. 10

FKBP6 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000077800. (Bottom) Encoded protein(s): isoform a, NP_003593.3; isoform b, NP_001128683.1; isoform c, NP_001268233.1. FKBP6 has a single and inactive N-terminal FKBP domain and a C-terminal TPR motif. For map legend, see Fig. 1

FKBP6, Function

GAPDH regulation FKBP6 is required in the initial step of the spermatogenesis, being only present in early stages of spermatocytes and not in spermatids. FKBP6 interacts with GAPDH through its TPR domain in an Hsp90-independent manner. FKBP6 controls GAPDH activity by either interfering with the NAD+ coenzyme binding or changing its subcellular distribution or reducing its expression. (Jarczowski et al. 2009).

Clathrin heavy chain FKBP6 binds directly to clathrin heavy chain and Hsp72 in testis cells and has a role in the disassembly of the clathrin coat during the maturation process of clathrin vesicles. FKBP6 lacks PPIase activity because of the presence of an Arg81 side chain on the active side, but its PPIase domain can interact with the clathrin heavy chain. By its TPR domain, it interacts with the C-terminal domain of Hsp72. FKBP6 and Hsp72 participate to the same process in male meiosis. The complex FKBP6–clathrin–Hsp72 is important for spermatocyte physiology (Jarczowski et al. 2008).

Small RNAs Epigenetic silencing of transposons by Piwi-interacting RNAs (piRNAs) constitutes an RNA-based genome defense mechanism. FKBP6, through its association with Hsp90, is implicated in the chaperone machinery in secondary piRNA biogenesis allowing turnover of Piwi complexes for their continued participation in piRNA amplification; moreover, FKBP6 has a role in the assembly of plant and fly microRNAs and siRNAs into the RISC complex (Xiol et al. 2012).

FKBP6 and Disease

Male infertility FKBP6 is an essential element for sex-specific fertility and the homologous chromosome pairing fidelity, during meiosis, through the regulation of the progression and/or maintenance of chromosome synapsis. The loss of FKBP6 (genomic deletion including exon 8) results in aspermic phenotype in rats (Crackower et al. 2003). Several SNPs of FKBP6 have been found significantly associated with oligozoospermia and/or azoospermia in a large cohort of European men (Aston et al. 2010).

HCV replication FKBP6 positively regulates viral genomic replication and the stability of the viral replication complex. FKBP6 interacts with the HCV nonstructural protein 5A (NS5A), affecting its phosphorylation state via Hsp90 and TPR domains. FKBP6 can dimerize with FKBP6 itself, or FKBP8, both critical for HCV replication. FKBP6 and/or FKBP8 provide specificity to the chaperone system for HCV replication. FKBP8 may be involved in the early stage of HCV infection, whereas FKBP6 may persistently support HCV replication after viral entry (Kasai H et al. 2015).

Williams–Beuren syndrome FKBP6 is deleted in Williams–Beuren syndrome and may contribute to hypercalcemia and growth delay in this dominant autosomal disorder (Meng X et al. 1998).

FKBP7

See Fig. 11.
FKBP (FK506 Binding Protein), Fig. 11

FKBP7 (Top) Focus on the locus of the gene. (Middle) The gene with exonic and intronic regions; ENSG00000079150. (Bottom) Encoded protein(s): isoform a, NP_851939.1; isoform b, NP_001128684.1. FKBP7 has two EF-Hand domains in the C-terminus and one FKBP domain at the N-terminus. For map legend, see Fig. 1

FKBP7, Function

Endoplasmic reticulum (ER) andimmunoglobulin-binding protein (BIP) FKBP7 is a glycoprotein with C-terminal Ca2+ binding sites that is retained in the ER by its carboxyl-terminal tetrapeptide His-Asp-Glu-Leu. FKBP7 binds to BiP in ER, a protein involved in protein folding or digestion of misfolded proteins or assembly of multichain protein molecules. Such binding involves both the C-terminus of FKBP7 and be Ca2+-dependent and its N-terminus, which can weakly bind BiP, in a Ca2+-independent manner (Zimmermann 1998). FKBP7/BiP complex has a negative effect on the ATPase domain of BiP. It is only when is bound to BiP, but not when it is free, that FKBP7 can suppress the ATPase activity of BiP, through catalyzing proline isomerization of the ATPase domain (Hamman et al. 1998).

FKBPL

See Fig. 12.
FKBP (FK506 Binding Protein), Fig. 12

FKBPL (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000204315. (Bottom) Encoded protein: isoform 1, NP_071393.2. FKPBL has C-terminal TPR domains. For map legend, see Fig. 1

FKBL, Function

Glucocorticoid receptor complex Unlike other members of the FKBP family, FKBPL shows low homology over the PPIase domain and lacks critical residues that have been shown to be required for enzymatic activity, but it is relatively well conserved at the TPR, which is functional in binding to HSP90. FKBPL co-localizes and interacts with the components of the HSP90–glucocorticoid receptor (GR) complex, the inactive PPIase domain is important for the interaction between this complex and the dynein motor protein, dynamitin. Treatment of DU145 cells with the GR ligand, dexamethasone, induced a rapid and coordinated translocation of both GR and FKBPL to the nucleus; this response was perturbed when FKBPL was knocked down. Furthermore, overexpression of FKBPL increased GR protein levels and transactivation of a luciferase reporter gene in response to dexamethasone. These responses are, however, cell line dependent (McKeen et al. 2008).

Angiogenesis The N-terminal region of FKBPL protein is responsible for the anti-angiogenic activity. The sequence is unique, with no homology to other FKBPs or other proteins. The anti-angiogenic mechanism is dependent on the interaction of secreted FKBPL with the cell-surface receptor CD44. Signaling downstream of this receptor inhibited endothelial cell migration (Valentine et al. 2011). FKBPL is secreted especially by human microvascular endothelial cells and fibroblasts. Proangiogenic hypoxic signals, but not the angiogenic cytokines, VEGF or IL8, downregulated FKBPL production. FKBPL knockout mouse shows embryonic lethality (Yakkundi et al. 2015).

FKBL and Disease

Male infertility FKBPL gene maps to chromosome 6p21.3, an area linked to azoospermia. FKBPL interacts with the androgen receptor complex and is strongly expressed in mouse testis, with expression upregulated during the puberty. The protein is expressed in human testis in a pattern similar to FKBP52 and also enhanced androgen receptor-mediated transcriptional activity in reporter assays. A study in 60 males with infertility showed a heterogeneous group of mutations, all absent in 56 controls (Sunnotel et al. 2010).

Cancer Following high-dose radiation stress, FKBPL binds to newly synthesized p21, in a complex with Hsp90, increasing p21 stability through prevention of its proteasomal degradation. This promotes the G2 arrest of cell cycle. FKBPL knockdown confers resistance to radiation, reasonably mediated by p21 downregulation (Bublik et al. 2010). FKBPL interacts with estrogen receptor. Stably overexpressing FKBPL breast cancer cells become highly sensitive to the antiestrogens tamoxifen and fulvestrant, whereas FKBPL knockdown reversed this phenotype. FKBPL expression was correlated with increased overall survival and distant metastasis-free survival in breast cancer patients. By increasing breast cancer sensitivity to endocrine therapies, FKBPL is thought to improve outcomes of this tumor (McKeen et al. 2010).

FKBP9

See Fig. 13.
FKBP (FK506 Binding Protein), Fig. 13

FKBP9. (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000122642. (Bottom) Encoded protein(s): isoform 1, NP_009201.2; isoform 2, NP_001271270.1; isoform 3, NP_001271272.1. FKBP9 has two EF-hand domains in the C-terminus and four FKBP domains at the N-terminus. For map legend, see Fig. 1

FKBP9, Function

Endoplasmic reticulum and sarcoplasmic reticulum FKBP9 contains a hydrophobic signal peptide at the N-terminus, four peptidyl-prolyl cis/trans isomerase (PPIase) domains and an endoplasmic reticulum retention motif (HDEL) at the C-terminus. This FKBP shares 66% sequence identity with FKBP6. The expression of FKBP9 is high in organs, including the heart, lung, skeletal muscle, and kidney, and is associated with Ca2+-related functions in the ER compartments. FKBP9 is involved in controlling the Ca2+ release into the cytosol, and its PPIase activity is important for protein folding and/or trafficking (Pan et al. 2010).

FKBP9 and Disease

Neurodegeneration FKBP9 has been found implicated in neurodegeneration, playing a role in the accumulation of misfolded protein aggregates or “prion-like” proteins’ seeding and spread (Brown et al. 2014).

Cardiac disease Catecholaminergic polymorphic ventricular tachycardia is a highly malignant autosomal recessive form of cardiomyopathy. Among the involved genes, seven are known to be cardiac- expressed, and FKBP9 is one of these, particularly involved in calcium ion handling (Bhuiyan et al. 2007).

AIPL1

See Fig. 14.
FKBP (FK506 Binding Protein), Fig. 14

AIPL1 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000129221. (Bottom) Encoded protein(s): isoform 1, NP_055151.3; isoform 2, NP_001028226.1; isoform 3, NP_001028227.1; isoform 4, NP_001272328.1; isoform 5, NP_001272329.1; isoform 6, NP_001272330.1; isoform 7, NP_001272331.1; isoform 8, NP_001272332.1. AIPL1 contains TPR domains. For map legend, see Fig. 1

AIPL1, Function

Aryl hydrocarbon receptor AIPL1 shares 49% identity with the human aryl hydrocarbon (Ah) receptor interacting protein (AIP). Both of them lack PPIase activity in vitro, but probably they are active in vivo only for very specific substrates. A polyproline-rich sequence of 56 amino acids is present at the C-terminus of human AIPL1. This unique proline-rich domain (PRD) is primate specific and important for chaperone function. Furthermore, PRD decreased the affinity of AIPL1 for Hsp90, implying that this domain acts as a negative regulator of the Hsp90 interaction. The AIPL1 similarity to AIP suggests that AIPL1 may be a component of a macromolecular heterocomplex that participates in retinal protein folding or cellular trafficking (Li et al. 2013).

NEDD8 ultimate buster protein 1 (NUB1) AIPL1 interacts with NUB1. NUB1 binds to and targets the ubiquitin-like proteins NEDD8. The AIPL1-binding domain of NUB1 consists of aa 569–584, overlapping with the NEDD8-binding site at aa 536–584 (Kanaya et al. 2004). Furthermore, AIPL1 and NUB1 form a ternary complex with FAT10, another ubiquitin-like modifier as NEDD8. AIPL1 acts to antagonize the NUB1-mediated proteasomal degradation (Bett et al. 2012).

Cyclic nucleotide phosphodiesterases (PDE) Cyclic nucleotide phosphodiesterases of the sixth family (PDE6) are the key effectors in the visual transduction cascade in rod and cone photoreceptors (Gopalakrishna et al. 2016). AIPL1 interacts specifically with the molecular chaperone HSP90 to modulate the stability and assembly of retinal cGMP phosphodiesterase (PDE6), and it is essential for photoreceptors survival (Ramamurthy et al. 2004). AIPL1 is also able to interact with and aid in the processing of farnesylated proteins. PDE prenylation is important for the maintenance of retinal and photoreceptor cytoarchitecture. AIPL1 is supposed to act by protecting the farnesylated protein from proteasomal degradation, or assisting in the biosynthesis or assembly of the PDE holoenzyme in a chaperone-like manner, or promoting the farnesylation of the PDE α subunit (van der Spuy et al. 2006).

AIPL1 and Disease

Leber’s congenital amaurosis (LCA) In human retina, AIPL1 is expressed during differentiation and development of the rod and cone photoreceptors. In Aipl1−/− retinas, rods, and cones quickly degenerate because of a reduction of cGMP hydrolytic activity and an increase of cGMP, thus inducing retinopathy (Liu et al. 2004). AIPL1 mutations cause Leber’s congenital amaurosis (LCA), a disease characterized by blindness or severe visual impairment at birth.

Retinitis pigmentosa Mutations in AIPL1 are found in autosomal dominant retinitis pigmentosa (RP) (Koenekoop 2004).

FKBP15

See Fig. 15.
FKBP (FK506 Binding Protein), Fig. 15

FKBP15 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000119321. (Bottom) Encoded protein: isoform 1, NP_056073.1. FKBP15 contains an FKBD and a domain similar to Wiskott–Aldrich syndrome protein homology region 1. For map legend, see Fig. 1

FKBP15, Function

Neuronal regulation FKBP15 contains a domain similar to Wiskott–Aldrich syndrome protein homology region 1 (WH1). FKBP15 protein, also known as WAFL, is distributed in the axonal shafts and the mouse homolog partially co-localize with F-actin in the growth cones of dorsal root ganglion neurons. FKBP15 overexpression increases the number of filopodia in the root ganglion neurons, while the overexpression of its mutant, deleted of the WH1 domain, reduces the growth of cone size and the number of filopodia (Nakajima et al. 2006).

Endocytosis FKBP15 is involved in the transport of early endosomes from the cell periphery to the perinuclear region, by interacting with actin filaments and microtubules (Pan et al. 2010). It interacts with two proteins that bind to the adaptor protein complex 2 (AP2), which acts as a hub in endocytosis mediated by clathrin-coated vesicle process. Endosomal localization of FKBP15 is regulated by the binding with proteins involved in actin cytoskeletal dynamics. A different distribution of FKBP15 and in its displacement from the endosome membrane results in defects of cell spreading and the cell shape (Harbour et al. 2012). FKBP15 increases during monocyte differentiation into macrophage, which is active in endocytosis for antigen processing.

FKBP15 and Disease

Ulcerative colitis is upregulated in the inflamed colonic mucosa of ulcerative colitis patients, probably because of the active endocytosis of immune cells involved in gut inflammation (Pan et al. 2010).

FKBP11

See Fig. 16.
FKBP (FK506 Binding Protein), Fig. 16

FKBP11 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000134285. (Bottom) Encoded protein(s): isoform 1: NP_057678.1; isoform 2: NP_001137253.1; isoform 3: NP_001137254.1. This protein possess one FKBP domain and an additional C-terminal helical structure and ER localization. For map legend, see Fig. 1

FKB11, Function

Osteogenesis FKBP11 interacts with interferon-inducible transmembrane protein 5 (IFITM5). This latter is an osteoblast-specific membrane protein whose expression peaks around the early mineralization stage, during the osteoblast maturation process. While IFITM5 interacts with several proteins in fibroblasts, in osteoblasts, FKBP11 is the only protein IFITM5 interacts with. The S-palmitoylation on IFITM5 promotes the interaction with FKBP11 (Hanagata et al. 2011).

FKB11 and Disease

Systemic lupus erythematosus (SLE) FKBP11 has been found to be overexpressed in B-cell transcriptome of quiescent SLE patients. Exogenous expression of FKBP11 reproduces by itself two phenotypic traits of SLE in the mouse, namely, loss of B-cell tolerance to self-DNA and initiation of plasma cell differentiation (Ruer-Laventie et al. 2015).

Hepatocellular carcinoma (HCC) Glycine N-methyltransferase (GNMT) knockout mouse develops HCC, and FKBP11 has been found to be an early marker for this type of HCC. FKBP11 expression levels progressively increased during the development of this tumor (Lin et al. 2013).

FKBP14

See Fig. 17.
FKBP (FK506 Binding Protein), Fig. 17

FKBP14 (Top) Locus on the chromosome. (Middle) The gene with exonic and intronic regions; ENSG00000106080. (Bottom) Encoded protein: NP_060416.1. FKBP14 possesses one FKBP domain, an additional C-terminal helical structure and ER localization. FKBP14 shares also two EF-hand domains, involved in calcium binding, with FKBP7, FKBP9, and FKBP10. For map legend, see Fig. 1

FKBP14, Function

Collagen synthesis Collagens contain a large number of proline residues that are posttranslationally modified to 3-hydroxyproline or 4-hydroxyproline. The rate-limiting step in the formation of the triple helix is the cis-trans isomerization of peptidyl-proline bonds. This step is catalyzed by peptidyl-prolyl cis-trans isomerases. FKBP14 catalyzes the folding of type III collagen and interacts with type III, VI, and X collagen (Shikawa and Bachinger 2014).

FKBP14 and Disease

Connective tissue disorder Deficiency of FKBP14 leads to enlarged ER cisterns in dermal fibroblasts in vivo and an altered assembly of the extracellular matrix in vitro. The absence of FKBP14 leads to a kyphoscoliotic type of Ehlers-Danlos syndrome and shows a wide spectrum of clinical phenotypes that include also myopathy, hearing loss, and aortic rupture (Baumann et al. 2012).

Glioblastoma multiforme FKBP14 is among the molecules downstream to epidermal growth factor receptor (EGFR) signaling pathway in glioblastoma multiforme and plays a role in glioblastoma resistance to erlotinib, a small molecule inhibitor of EGFR tyrosine kinase activity (Halatsch et al. 2008).

Summary

FKBP is a subfamily of proteins exerting peptidyl-prolyl isomerase (PPIase) activity, with exceptions of FKBP6, FKBP8, and AIP. Together with the structurally dissimilar cyclophilins, they belong to the larger protein family of immunophilins. The FKBPs share with cyclophilins the PPIase activity. Such activity, in FKBP, is inhibited by FK506 or rapamycin, while, in cyclophilins by cyclosporin. Most of the FKBPs are multi-domain proteins encompassing several functions, including one or more PPIase domain, which shows high sequence homology with the firstly discovered FKBP12. The simplest FKBPs are made up of a single FKBP domain, which exerts the most and firstly known function, the peptidyl-prolyl cis-trans isomerase (PPIases) activity. This ability to convert proline bonds from cis-to-trans form of Xaa-Pro peptide bond occurs through binding of a peptide substrate in the hydrophobic binding pocket of the PPIase. The domain by which this activity is explicated is known also as PPIase domain, FK506 binding domain (FKBD) or FK domain, due to its ability to bind FK506 and rapamycin. The group of simplest FKBPs includes FKBP1A and 1B. The other FKBPs contain one or more FKBDs (with exception of FKBPL and AIP1L) and additional functional units: signal peptides responsible for membrane association or ER localization (FKBP2, FKBP11, and FKBP14), EF-hand domains (FKBP7, FKBP9, and FKBP10), helix-loop-helix motifs to DNA binding (FKBP3), putative calmodulin-binding domain (FKBP8), transmembrane motifs (FKBP8), ATP-/GTP-binding domains (FKBP4, FKBP5), and tetratricopeptide domains (TPR) (with exception of FKBP1A, FKBP1B, FKBP2, FKBP3, FKBP7, FKBP9, FKBP10, FKBP11, FKBP14, FKBP15). The TPR domain is mainly responsible for the chaperone activity and able to recognize nonnative proteins, prevent unwanted inter- and intramolecular interactions, and influence the partitioning between the productive and unproductive folding steps. TPR domain is also important for the interaction with heat shock protein 90 (HSP90) which, in turn, mediates wider interactions with different proteins in the cell. FKBPs are conserved from yeast to animals. Seventeen FKBPs have been so far identified in human. In the last decades, several studies assign to the growing family of FKBPs an increasing number of biological roles, mediated through protein–protein interaction. Similarly, an increasing number of studies involve FKBPs in the etiology/pathogenesis of human diseases, including cancer (Romano et al. 2015b).

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Paolo D’Arrigo
    • 1
  • Martina Tufano
    • 1
  • Anna Rea
    • 1
  • Simona Romano
    • 1
  • Maria Fiammetta Romano
    • 1
  1. 1.Department of Molecular Medicine and Medical BiotechnologyUniversity of Naples “Federico II”NaplesItaly