Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Sorcin

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101842

Synonyms

Historical Background

The short isoform of Sorcin (soluble resistance-related calcium-binding protein) (a 19,000-dalton peptide) was isolated for the first time by Meyers and coworkers in vincristine-resistant Chinese hamster cells (DC-3FVCRd-5). A similar protein (Mr = 19,000; pI = 5.7) was also found in a vincristine-resistant mouse line (Meyers and Biedler 1981). The gene of Sorcin (SRI) codifying for the longest isoform was identified around the multidrug resistance gene region of human chromosome 7q21.1.

The gene can generate at least four alternative transcripts, i.e., isoforms A (a primary transcript of 15 kb divided in eight exons and seven introns, transcribed in a 198-amino-acid-long protein), B, C, and D, yielding shorter forms of the protein, lacking part of the N-terminal domain and/or of the final residues of the C-terminal domain. The isoform A was identified by Van der Bliek et al., who disclosed its homology with the light chain of calpain (Van der Bliek et al. 1986).

Sorcin is a penta-EF-hand (PEF) protein formed by two different domains, i.e., the flexible, glycine-rich N-terminal domain (residues 1–33) and the calcium-binding domain (residues 34–198), which contains five EF hands. The EF hand is a structural motif characterized by a helix-loop-helix structure, used by a large number of proteins to bind calcium with high affinity. In the “canonical” motif, the calcium ion is coordinated by a 12-amino-acid-long inter-helical loop with pentagonal bipyramidal symmetry. In this arrangement, four conserved side chains provide the five equatorial ligands (Y, Z, −Y, −Z), since the glutamate residue in position -Z establishes a bidentate interaction with the metal. The two apical ligands are furnished by the side chain of an acidic group (X) and by a water molecule (−X) (Table 1).
Sorcin, Table 1

Calcium coordination residues in the highest affinity EF hands (EF1, EF2, EF3) of PEF family members

  

X

Y

Z

−Y

−X

−Z

Sor

aEF1

Ala43

H2O

Asp46

H2O

Gln48

Glu53

(O)

(OD1)

(Asp50)

(O)

(OD1, OD2)

Grancalcin

EF1

Ala62

Asp65

Glu67

Glu72

PDCD6

aEF1

Asp36

Asp38

Ser40

Val42

H2O

Glu47

(OD1)

(OD1)

(OG)

(O)

(OD1, OD2)

Sor

aEF2

Asp83

Asp85

Ser87

H2O

Thr89

Glu94

(OD1)

(OD1)

(OG)

(Gln48)

(O)

(OD1, OD2)

Grancalcin

EF2

Asp(102)

Asp(104)

Thr(106)

Lys(108)

Ala(113)

PDCD6

EF2

Asp(73)

Glu(75)

Lys(77)

Gly(79)

Glu(84)

Sor

aEF3

Asp113

Asp115

Ser117

H2O

Thr119

Glu124

(OD1)

(OD1)

(OG)

(Asp121)

(O)

(OD1,OD2)

Grancalcin

aEF3

Asp132

Asp134

Ser136

Thr38

Glu143

(OD2)

(OD1)

(OG)

(O)

(OD1,OD2)

PDCD6

aEF3

Asp103

Asp105

Ser107

Met109

Glu114

(OD1)

(OD2)

(OG)

(O)

(OD1, OD2)

Comparison between Alg2 (PDCD6) (Pdb code 2ZN9) belonging to the group I and Sorcin and grancalcin (Pdb code 1F4O) belonging to group II

In 2ZN9 only the EF1 and EF3 loops are occupied by calcium ions, whereas in 1F4O only the EF3 loop is occupied by calcium ion

aOnly the loops marked are compared on the basis of the three-dimensional structures

Sorcin is widely distributed in vertebrates, and its amino acid sequence is highly conserved among species. The protein sequences of the mouse and human Sorcin show only eight differences, concentrated in the second half of the protein, and six of them concern phosphorylatable (serine and threonine) residues, an indication that species-specific phosphorylation-dependent regulation of Sorcin may take place.

Sorcin, upon calcium binding, undergoes a conformational change allowing it to interact with its molecular targets (Meyers et al. 1995).

Maki and coworkers classified PEF proteins on the basis of the primary structures of EF1 hand Ca2+-binding loops. Group I proteins, i.e., ALG-2 (PDCD6), peflin, and their homologs, possess a canonical 12-residue EF1 loop, while group II proteins (Sorcin, grancalcin, and calpains) possess a shorter 11-residue EF1 loop. The human group II PEF proteins have introns at almost identical positions. The one-residue deletion sites in the EF1 Ca(II)-binding loops coincide with the positions of introns (for instance, between LAGD-111 and 112-DMEV of CAPNS calpain). Group II PEF protein genes have possibly originated from group I PEF protein genes during the course of evolution from invertebrates to vertebrates (Maki et al. 2002).

Sorcin Structure

In the years 2001–2002, two different groups solved the X-ray structure of human Sorcin (Xie et al. 2001) (2.2 Å resolution, PDB code, 2JUO) and of the hamster Sorcin calcium-binding domain (Ilari et al. 2002) (2.2 Å resolution, PDB, 1GJY) in the apo forms. Finally, in 2015 Ilari and coworkers solved the X-ray crystal structures of human Sorcin in complex with calcium (CaSor, 1.65 Å resolution, 4USL) and in the apo form (apoSor, 2.1 Å resolution, 4UPG) (Ilari et al. 2015). Sorcin is a homodimer; each monomer contains a Gly-rich flexible N-terminal domain (residues 1–32, partially visible in the CaSor structure (residues 26–32) and the calcium-binding domain (SCBD, residues 33–198). The SCBD contains eight α-helices (A–H) organized in five calcium-binding motifs (EF1-EF5). The D-helix is common to EF2 and EF3, while the G-helix is common to EF4 and EF5. Usually EF hands are structurally and functionally coupled. Sorcin has EF1-EF2 and EF3-EF4 pairs, while the EF5 hands of the two monomers pair to form the dimeric interface, stabilized by hydrophobic interactions between side chains, which include three phenylalanine residues of both subunits (F186, F191, F173).

Sorcin exists in two different conformations: the closed conformation (apo) and the open conformation (calcium bound) that allows the protein to interact with its molecular partners (Fig. 1 panels a–c). The transition from the closed to the open conformation takes place upon binding of three calcium ions to the high-affinity EF hands (EF1, EF2, and EF3, which are the sites endowed with the highest affinity) (Fig. 2 panels a, b); the ion binding induces a large displacement of the D-helix (21°) (Fig. 1c). In particular, the binding of calcium to EF3 causes the movement of the three residues Asp113, Asp115, and Ser117 toward the bidentate Glu124 ligand, with the consequent rearrangement of the EF3 acting as a lever dragging the long and rigid D-helix away from the E-helix. As a result, EF3 acts as a pivot: the first half of the calcium-binding domain (formed by A-, B-, C-, and D-helices) rotates and moves away from the second half (formed by the E-, F-, G-, and H-helices), which is the dimerization subdomain and forms the stable Sorcin dimeric interface (Fig. 2a).
Sorcin, Fig. 1

Human Sorcin monomer overall fold. (a) Human Sorcin in the apo form. The α-helices are indicated. (b) Human Sorcin in the Ca2+-bound form. The five EF hands are indicated. (c) Superimposition between the human Sorcin in the apo (red) and Ca2+-bound (blue) forms. The calcium ions are represented as sphere and colored yellow. The pictures are depicted using PyMol

Sorcin, Fig. 2

(a) The dimeric structure of Sorcin in the Ca2+-bound form. The two monomers are colored in orange and blue. The calcium ions are represented as sphere and colored yellow. (b) The two structurally coupled Sorcin EF hands EF1 and EF2. The residues coordinating the calcium ions are indicated and depicted as sticks. (c) The highest Ca2+ affinity EF hand: EF3. The residues coordinating the calcium ions are indicated and depicted as sticks. The water molecules are represented as red spheres. The calcium ions are represented as sphere and colored yellow. The pictures are depicted using PyMol

The analysis of solvent accessible surface areas performed by Ilari and coworkers (Ilari et al. 2015) shows that upon calcium binding, there is an increase in the exposed surface areas of several residues. The residues with a difference in SASA (solvent accessible surface areas) higher than 30% between the apoSor and CaSor (Tyr67, Ser80, Met81, Met86, Ile110, Arg116, Gly118, Ser143, and Ser197) are located in the loops respectively preceding the C-helix, in the EF2 loop (which follows the C-helix), in the C-terminal part of the D-helix, and in the EF3 loop (Fig. 3a). Calcium binding has almost no effect on the relative position of C- and D-helices of the EF2 hand, but it promotes a reorganization of the last part of the C-helix containing Met81 and of the loops 83–91 containing Met86, which becomes exposed to the solvent. Moreover, the interaction between Tyr67, placed on the loop between helices B and C, and Asp113 placed on the EF3 loop in apoSor, is broken upon calcium binding, since Asp113 participates in ion coordination. Finally, the rearrangement of the EF3 loop causes also the exposure of Arg116.
Sorcin, Fig. 3

Solvent accessible surface analysis and hot spot prediction. (a) The residues that upon calcium binding become more exposed to the solvent (SASA increase higher than 30%) are indicated and depicted as sticks. (b) Hotpatch analysis. The residues lining the three pockets identified pocket 1, pocket 2, and pocket 3 are colored in magenta, red, and orange, respectively, and depicted as sticks

The Hotpatch structural analysis on CaSor structure allowed identification of unusual hydrophobic patches likely mediating protein-protein interactions between Sorcin and its molecular partners. This analysis brought out the existence of three pockets (pockets 1, 2, and 3) lined by the following residues: His108 and Met132 (pocket 1); Met81, Val101, Trp105, and Val164 (pocket 2); and Ala26, Phe27, Pro28, Pro34, Leu35, Tyr36, Gly37, Tyr38, Ser61, and Trp99 (pocket 3) (Fig. 3b). Interestingly, these clusters are found in the areas most affected by calcium-dependent structural changes, namely, EF1 and EF3, and include tryptophan residues (Trp99 and Trp105) strongly conserved among the PEF protein family members (Ilari et al. 2015). Colotti and coworkers previously demonstrated that mutation of Trp105 impairs the capacity of Sorcin to recognize and interact with RyR2 and annexin7 at physiological calcium concentrations (Colotti et al. 2006).

Sorcin Interaction with Molecular Partners

In the PEF family, the extensively modified EF4 and EF5 loops do not bind Ca2+, the latter forming the dimeric interface of the homodimer. The X-ray structure of CaSor shows that the protein can bind up to three molecules of calcium at the EF1, EF2, and EF3 calcium-binding sites (Fig. 1c). Site-specific mutagenesis studies show that the affinity of the three EF hands follows the order EF3>EF2>EF1 (Mella et al. 2003). As shown by the X-ray structures, the binding of calcium to EF3 causes a large conformational change involving the movement of long and rigid D-helix away from the E-helix, which exposes hydrophobic surfaces available for the interaction with Sorcin molecular partners. The electronic density map of the CaSor X-ray structure reveals the presence of an electron density peak in the cavity formed upon calcium binding and the consequent tilt of the D-helix that was fitted with the GYYPGG hexapeptide belonging to the N-terminal region of Sorcin (residues 12–17) from a different dimer in the crystal (Fig. 4). The residues of the D-helix play a major role in interacting with the N-terminal peptide; in particular, Trp105 (pocket 1) establishes a strong stacking interaction with Pro15 and is hydrogen bonded to the carbonyl group of Tyr13, determining the orientation of the peptide into the pocket. Phage display analysis revealed that most ligands interacting with Sorcin contain a conserved Pro and that the main consensus motif is a relaxed Φ /Gly/Met-Φ/Gly/Met-x-P, where Φ is an aromatic residue (Trp, Tyr, or Phe).
Sorcin, Fig. 4

Sorcin mode of interaction. Blowup of the 12-GYYPGG-17 peptide-binding region: the peptide is colored orange and depicted as sticks. The residues interacting with the peptide are indicated and depicted as sticks

These findings suggest a mode of binding of a class of Sorcin interactors previously identified, which possess an N-terminal domain containing Φ/Gly/Met-Φ/Gly/Met-x-P-binding motifs. Two of them (annexin7 and annexin11) colocalize with Sorcin in the midbody of 3T3-L1 fibroblasts during cytokinesis.

Sorcin is expressed in a wide set of human cell types, such as cardiac cells, vascular smooth muscle cells, and adrenal medulla, and participates in the regulation of a variety of cell-specific calcium-dependent functions. In cardiac and smooth muscle cells, Sorcin upon calcium binding interacts with the ryanodine receptor 2 (RyR2), the Na+-Ca2+ exchanger NCX1, the L-type voltage-dependent Ca2+ channel (LTCC), and the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) and regulates these proteins.

Matsumoto and coworkers (Matsumoto et al. 2005) showed that in cardiomyocytes overexpressing Sorcin (by means of an adenovirus-mediated gene delivery method), both SERCA2 activity and calcium uptake to sarcoplasmic reticulum (SR) are increased with respect to normal cells.

Fowler (Fowler et al. 2009) demonstrated that Sorcin speeds up inactivation of LTCC in isolated rabbit ventricular myocytes, whereas downregulation of endogenous Sorcin slowed inactivation the LTCC calcium current.

Zamparelli and coworkers (Zamparelli et al. 2010) demonstrated that Sorcin is able to activate the sarcolemmal NCX1 exchanger; Sorcin supplementation increases NCX1 activity, whereas downregulation of Sorcin decreases its activity. The direct interaction between Sorcin and the calcium-binding domains of NCX1 (CBD1 and CBD2) was demonstrated by using surface plasmon resonance (SPR) technique that allowed the measurement of the KD constants in the low micromolar range.

Finally, the interaction between Sorcin and RyR2 was the first to be investigated (Lokuta et al. 1997), using purified recombinant Sorcin in [3H]ryanodine-binding experiments and single-channel recordings of RyR. The open probability of single RyR was decreased significantly by the addition of Sorcin to the cytoplasmic side of the channel.

Sorcin interacts with many other targets, among which are several serine-threonine kinases participating in the regulation of mitosis progression. Sorcin contains several potential phosphorylation sites, and phosphorylation contributes to regulate its activity. Recently, Lalioti and coworkers discovered that Sorcin is phosphorylated by polo-like kinase 1 (Plk1), induces Plk1 autophosphorylation, and contributes to Plk1 regulation (Lalioti et al. 2014). Other kinases such as cAMP-dependent protein kinase (PKA) and calcium-calmodulin-dependent kinase II (CaMKII) phosphorylate Sorcin, altering Sorcin binding to RyRs and SERCA and, therefore, calcium homeostasis (Colotti et al. 2014).

Role of Sorcin in the Excitation-Contraction Coupling Process

In the heart, Ca2+-bound Sorcin localizes mostly in the T-tubules and at the SR, modulating calcium-induced calcium release (CICR) and excitation-contraction coupling through the interaction with important cardiac calcium channels such as RyR2, NCX1, LTCC, and SERCA. All these interactions appear to concur functionally and are presumed to help terminate CICR in ventricular myocytes.

The importance of Sorcin was supported by the discovery that a natural substitution of Phe112 with a leucine residue determines in the individuals carrying the mutation a hypertrophic cardiomyopathy and hypertension. Structural studies on the Sorcin F112L mutant allowed the comprehension of the molecular basis of Sorcin dysfunction. Indeed, the X-ray structure shows that the F112L mutation involves a residue located at the end of the D-helix, close to the EF3 hand, and next to Asp113, one of the acidic residues in EF3 that bind calcium with the highest affinity (Franceschini et al. 2008). The comparison between the structures of wild-type and F112L Sorcin shows that the mutation determines a large conformational change and leads to a decrease in calcium affinity. The mutation disrupts an important component of the hydrogen bonding network around the D-helix, i.e., the interaction between the Phe112 carbonylic oxygen and the Glu124 carboxylate (the bidentate Ca2+ ligand in the EF3 hand), thereby impairing the EF3 triggering function. As a consequence, a shift of the D-helix takes place, with a 30° rotation of EF2 with respect to EF3. The most dramatic change in the F112L structure vs. the wild-type protein concerns the EF1 motif, which is rotated 180° around Tyr67, located in the loop between the B and C helices.

The structural changes in the F112L natural variant are reflected in the sixfold decrease in calcium affinity and in a diminished capacity to interact with annexin7 and RyR2, with a loss of function possibly causing hypertrophic cardiomyopathy and hypertension.

Role of Sorcin in Resistance to Chemotherapeutic Drugs

Sorcin (soluble resistance-related calcium-binding protein) gene is located in the same chromosomal locus and amplicon as the ABC transporters MDR1 and MDR3, both in human and rodent genomes (two variants of MDR1, i.e., of MDR1a and MDR1b, are within the rodent amplicon). Sorcin was initially labeled “resistance related,” since it is coamplified with MDR1 in multidrug-resistant cells (Van der Bliek et al. 1986). While for years Sorcin overproduction was believed to be a by-product of the coamplification of its gene with P-glycoprotein genes (Van der Bliek et al. 1988), a number of recent reports have demonstrated that Sorcin plays a role in multidrug resistance (MDR) and pointed at a possible role as an oncoprotein.

Sorcin is one of the most highly expressed calcium-binding proteins in many tissues and part of the 5% most expressed proteins of the human proteome (source PaxDb). Importantly, Sorcin is overexpressed in many human tumors, such as leukemia, lymphoma, and adenocarcinoma; gastric, lung, breast, nasopharyngeal, and ovarian cancers; and astrocytoma, oligodendroglioma, glioblastoma, and especially in MDR cancers (for a review, Colotti et al. 2014). The level of Sorcin expression in leukemia patients inversely correlates with patients’ response to chemotherapies and overall prognosis. In parallel, Sorcin is highly expressed in chemoresistant cell lines and significantly upregulated in doxorubicin-induced MDR leukemia cell line K562/A02 over its parent cells.

Sorcin overexpression by gene transfection increased drug resistance to a variety of chemotherapeutic agents (e.g., doxorubicin, etoposide, homoharringtonine, and vincristine) in K562 cells; Sorcin overexpression determined drug resistance (to vincristine, Adriamycin, Taxol, and 5-fluorouracil) in SGC7901 cells and ovarian and breast cancer. On the other hand, several recent studies have demonstrated that inhibition of Sorcin expression by RNA interference led to reversal of drug resistance in a number of cell lines (for a review, Colotti et al. 2014).

Further, Sorcin silencing inhibits the epithelial-to-mesenchymal transition (EMT) in breast cancer MDA-MB-213 cell line, possibly via E-cadherin and VEGF expression, and reduces breast cancer metastasis, whereas Sorcin overexpression increases migration and invasion in vitro (Tong et al. 2015).

Sorcin Localization and Function in the Cell

Sorcin is expressed in most human tissues and, according to MOPED, PaxDb, and MaxQB databases, is expressed at high levels in the bone, heart, brain, B and T lymphocytes, monocytes, kidney, breast, and skin. Sorcin changes its localization during the cell cycle. During interphase Sorcin localizes in the nucleus, in the cytosol, in the plasma membranes, at the endoplasmic reticulum (ER), and in ER-derived vesicles localized along the microtubules containing Sorcin interactors such as RyR2, SERCA, calreticulin, and Rab10. During late telophase Sorcin migrates to the cleavage furrow and at the midbody before cytokinesis (Lalioti et al. 2014).

In the cytosol, calcium homeostasis is controlled and calcium concentration is maintained in the range 10–100 nM by calcium-binding proteins with different mechanisms: the regulation of the activity of calcium channels which actively pump out calcium from the cytosol to the extracellular space, into ER and/or mitochondria, and the direct binding of the cation which contributes to the calcium buffering process. Sorcin participates in the regulation of calcium homeostasis by both mechanisms. Indeed Sorcin binds calcium in the micromolar range and upon calcium binding interacts with RyR2 and SERCA, located in the ER, and with LTCC and NCX, located in the plasma membrane, and regulates them. In particular, Sorcin increases calcium accumulation in the ER by activating SERCA and by inhibiting RyR2, increases dimensions and calcium load of ER-derived vesicles, and is also able to increase mitochondrial calcium concentration.

High Sorcin expression has a protective effect on ER, i.e., Sorcin overexpression increases ER calcium concentration, prevents ER stress and the unfolded protein response, and diminishes apoptosis. Conversely, Sorcin silencing elicits profound effects on cell growth, mitosis, and cytokinesis, blocks cell cycle progression in the G2/M-phase of mitosis, increases the number of rounded polynucleated cells, and activates proteases as caspase-3, caspase-12, and GRP78/BiP, inducing apoptosis and cell death.

Sorcin has been identified in other vesicles than the ER-dependent ones, such as in nanovesicles containing annexin7, released in a calcium-dependent manner from the erythrocytes, and in exosomes from different sources, such as B-cell exosomes, mesenchymal stem cell exosomes, and exosomes from human urine.

Sorcin has also other possible signaling roles, linking calcium levels with different metabolisms. Sorcin binds to and sequesters the carbohydrate-responsive element-binding protein (ChREBP) in the cytosol at low glucose, by interacting with the N-terminal glucose-sensing domain of ChREBP (Noordeen et al. 2012). Following glucose stimulation and calcium influx, Sorcin releases ChREBP, which becomes free to translocate to the nucleus. In addition, it influences mitochondrial calcium levels and interacts with TRAP1 in the mitochondria, cooperating in a survival pathway (Maddalena et al. 2011).

Summary

Sorcin is a calcium-binding protein isolated in the multidrug resistant cell. As all PEF proteins, it is formed by two subunits: the flexible Gly-rich N-terminal domain and the calcium-binding domain (SCBD). Sorcin is able to bind calcium with three high affinity calcium-binding motifs (EF1–3) in the micromolar range. Upon calcium binding Sorcin undergoes a conformational change, involving a large movement of the D-helix, which discloses hydrophobic surfaces allowing its interaction with molecular partners. Sorcin is expressed at high levels in the bone, heart, brain, B and T lymphocytes, monocytes, kidney, breast, and skin; it is overexpressed in many cancer types, such as leukemia, lymphoma, and adenocarcinoma, and in many multidrug resistance (MDR) cancers and participates in the generation of the MDR phenotype. Sorcin regulates calcium homeostasis by binding and regulating RyR2, SERCA, LTCC, and NCX. In particular, Sorcin increases calcium accumulation in the ER by activating SERCA and by inhibiting RyR2. Thus, high Sorcin expression has a protective effect on ER, since Sorcin overexpression increases ER calcium concentration and prevents ER stress and the unfolded protein response. Conversely, Sorcin silencing elicits profound effects on cell growth, mitosis, and cytokinesis, blocks cell cycle progression in the G2/M-phase of mitosis, and induces apoptosis.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Molecular Biology and Pathology, c/o Department of Biochemical Sciences, Sapienza University of RomaItalian National Research Council (CNR)RomeItaly