Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Torsin 1A Interacting Protein 1

  • Joana B. Serrano
  • Filipa Martins
  • Ana M. Marafona
  • Odete A. B. da Cruz e Silva
  • Sandra Rebelo
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101846


Historical Background

Lamina associated polypeptide 1 (LAP1) was identified in 1988 as an integral inner nuclear membrane (INM) protein associated with lamins. LAP1 family members were identified using a monoclonal antibody against rat liver nuclear envelope (NE) extracts (Senior and Gerace 1988). This antibody recognized three polypeptides with apparent molecular weights of 75 KDa, 68 KDa, and 55 KDa in rat liver NEs that were subsequently termed LAP1A, LAP1B, and LAP1C, respectively. The evidence that LAP1 was connected to nuclear lamina was achieved by biochemical extraction experiments, and subsequent in vitro experiments demonstrated that LAP1A and LAP1B bind directly to lamins A, C, and B1 and most likely indirectly to chromosomes (Foisner and Gerace 1993). Further co-immunoprecipitation studies demonstrated that LAP1A/LAP1C co-immunoprecipitated with B-type lamins (Maison et al. 1997).

The first full-sequenced cDNA of LAP1 was determined in 1995 and was referent to rat LAP1C. Partial characterization of the other cDNAs suggested that the three rat LAP1 family members result from alternative splicing, given that LAP1A and LAP1B were identical to the LAP1C sequence, having only two insertions. Subsequently further characterization of LAP1C was achieved. It was shown that LAP1C is a type II transmembrane protein, containing a nucleoplasmic N-terminal domain, a single transmembrane (TM) domain, and a luminal C-terminal domain located in the perinuclear space (Martin et al. 1995).

The first human full-length cDNA of LAP1 was only reported in 2002. LAP1B was isolated from an expression library of HeLa cells and presented around 74% amino acid identity with the predicted rat LAP1B. Further, human LAP1B comprises a single TM domain, and interestingly the lumenal and the nucleoplasmic domain present 89% and 66% amino acid identity with the predicted rat LAP1B, respectively (Kondo et al. 2002). Further, a splice variant of LAP1B was also reported (Tadokoro et al. 2005). Recently, a novel human LAP1 isoform was identified and named LAP1C. This novel human isoform was shown to be present in both human cell lines and tissues (Santos et al. 2014). Both human LAP1B and LAP1C are integral proteins of the inner nuclear membrane (INM).

Human TOR1AIP1 Gene, Transcripts, and Isoforms

In terms of structure the torsin A interacting protein 1 (TOR1AIP1) gene (gene encoding LAP1) is composed by ten exons (Fig. 1). The diversity of human LAP1 proteins was previously reported using in silico analysis of TOR1AIP1 gene (Santos et al. 2014). In summary, two human LAP1 transcripts were found in the GenBank database: transcript variants 1 and 2. Transcript variant 1 (NM_001267578) represents the longest transcript and is similar to the first human LAP1B sequence reported by Kondo et al. (2002), which results in a 584 amino acid (aa) long protein with molecular weight of 68 KDa. Transcript variant 2 only differs from transcript variant 1 by a CAG deletion, resulting in an alanine deletion from the coding sequence (Fig. 1). This corresponds to the LAP1B splice variant identified by Tadokoro et al. (2005), which results in a 583 aa long protein. Further, searches in the GenBank database for additional human LAP1 ESTs, allowed for the identification of non-RefSeq mRNA records (BC023247, AK023204, and AK021613) that lack the 5′ end region of exon 1. The analysis of these sequences revealed that the start codon present in LAP1B is absent, but an additional in frame ATG is present downstream at position 363 (nucleotide sequence), and consequently this alternative start codon is located at position 122 (aa sequence). The in silico analysis combined with experimental characterization of the LAP1 transcripts permitted identifying the human LAP1C isoform (Santos et al. 2014). LAP1C has a shorter N-terminal domain when compared with LAP1B and appears to result from an alternative translational initiation with a downstream in frame start codon at position 122 (aa sequence), previously mapped by in silico characterization and also represented in Fig. 1. As a consequence of this alternative translational initiation, a 482 aa long protein is originated with a molecular weight of 58 KDa.
Torsin 1A Interacting Protein 1, Fig. 1

Structure of the humanTOR1AIP1gene, transcripts variants, and LAP1 isoforms. The human TOR1AIP1 gene, located at chromosome position 1q25.2, contains ten exons. Coding exons are represented by white line running across the boxes, while noncoding sequences in exons are represented by opaque boxes. The inframe ATG codons are indicated by arrows. Human LAP1B transcript variants differ only in exon 3 (black box) by three nucleotides (CAG), generated through an alternative 3′ splicing event. Human LAP1C predicted transcript results from an alternative translational initiation. The three human LAP1 isoforms contain an N-terminal nucleoplasmic domain, a transmembrane domain, and a C-terminal luminal domain. The LAP1B isoform 2 (583 aa) differs from LAP1B isoform 1 (584aa) by an alanine deletion resulting in a shorter protein. Human LAP1C isoform (462 aa) presents a shorter N-terminal when compared with both LAP1B isoforms. TM, transmembrane domain; LAP1C*, predicted LAP1C transcript

The physiological relevance of the LAP1 different isoforms is unknown but some ideas are emerging. LAP1 is ubiquitously expressed in neuronal and nonneuronal tissues (Goodchild and Dauer 2005). Moreover, LAP1A, LAP1B, and LAP1C are detected in liver, spleen, brain, and kidney rat tissues, but LAP1A seems to be the major isoform present in rat liver. LAP1C is the major isoform detected in rat-cultured cells (Senior and Gerace 1988). In human cell lines, this is also true, being that LAP1C is more abundant than LAP1B. However, in human tissues, the expression of LAP1B/LAP1C ratio was found to be tissue specific. Briefly, the expression of both human LAP1B and LAP1C was quite similar in both testis and ovary, and this is in sharp contrast with other tissues like the lung, kidney and spleen, where LAP1C was more abundant than LAP1B. Interestingly, the expression of human LAP1B was higher than LAP1C in the brain and heart (Santos et al. 2014).

TOR1AIP1 Mutations

The first TOR1AIP1 mutation was reported in a consanguineous Turkish family (“Turkish” mutation), where three affected individuals present proximal and distal weakness and atrophy, rigid spine, and joint contractures. Additionally, to this muscular dystrophy, a cardiomyopathy and respiratory involvement were observed. The c.186delG mutation was located in the first exon resulting in a nucleotide deletion (and correspondent amino acid deletion: p.E62delG) that is predicted to cause a frameshift and a premature stop codon (Kayman-Kurekci et al. 2014; Rebelo et al. 2015a) and the generation of a truncated protein (Fig. 2a). Consequently, the 584 aa LAP1 protein is absent and a protein of 83 aa long is generated (Fig. 2b). Ultrastructural and molecular analysis of the muscle fibers confirmed that the LAP1B protein is absent in the patient’s myonuclei. Apparently the mutant RNA is eliminated by nonsense-mediated decay, and the truncated protein is nonfunctional. However, LAP1 was not absent in all tissues, as predicted. It was shown that another LAP1 isoform is present in endomysial cells that correspond to the additional band of approximately 50 KDa. This band corresponds to human LAP1C isoform with an apparent molecular weight of 56 KDa (Santos et al. 2014). Interestingly, these patients express high levels of LAP1C when LAP1B is absent. Therefore, this form of muscular dystrophy seems to be associated with the LAP1B isoform and cannot be compensated for by the expression of the LAP1C isoform, suggesting a distinct function for each of the isoforms. The study performed by Kayman-Kurekci et al. (2014) increases the number of genes associated with nuclear envelopathies and points to LAP1B as a key protein for striated muscle function.
Torsin 1A Interacting Protein 1, Fig. 2

HumanTOR1AIP1mutations. (a) Representation of human TOR1AIP1 gene mutations. The “Turkish” mutation results from a single nucleotide deletion (c.186delG, represented in gray) producing an early stop codon. The “Moroccan” mutation results from a nucleotide substitution (c.1448A>C, represented in black). The first “Australian” mutation results from a frameshift mutation in exon 1 (c.127delC, represented in red), and the second results from a missense change in exon 10 (c.1181T>C, represented in red). (b) Representation of the resulting human mutated LAP1B proteins. The “Australian” mutation results in a truncated LAP1B protein of 58 amino acids, lacking the TM domain, and is putatively nonfunctional. The “Turkish” mutation results in a shorter LAP1B protein with 83 amino acids. The “Moroccan” mutation results in a glutamic acid substitution by an alanine at position 482 of LAP1B peptide. The position of each mutation is indicated by a colored arrow (same color used to indicate the gene alteration)

A second TOR1AIP1 mutation was reported in a boy, born from consanguineous healthy parents (“Moroccan” mutation), who developed rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy (Dorboz et al. 2014). The patient’s whole exome sequencing revealed a homozygous missense mutation (c.1448A>C) in the TOR1AIP1 gene that results in the change of a glutamic acid to an alanine at amino acid position 482 (p.E482A) (Dorboz et al. 2014; Rebelo et al. 2015a) (Fig. 2). Of note, this glutamic acid is a highly conserved residue. Using the patient’s fibroblasts, the authors demonstrated that this individual presented reduced LAP1 levels and altered subcellular distribution. A strong reduction of LAP1 at the NE was observed with a concomitant mislocation and aggregation of LAP1 at the endoplasmic reticulum (ER) (Dorboz et al. 2014). Of note, given the position of the mutation, apparently both LAP1 human isoforms (LAP1B and LAP1C) are affected.

Additionally, two novel pathogenic TOR1AIP1 mutations have been recently reported (Ghaoui et al. 2016). In this case, two siblings from an Australian family (“Australian” mutation) revealed severe cardiac failure, musculoskeletal weakness, and muscular dystrophy. The whole genome sequencing of the affected siblings showed a frameshift mutation in exon 1 (c.127delC, p.Pro43fs*15) resulting in a truncated protein of 58 amino acids, lacking the TM domain, and is putatively nonfunctional (Fig. 2). Consequently, no LAP1B is observed in these patients. The second mutation is a missense change in exon 10 (c.1181T>C, p.L394P) that is predicted to be very pathogenic (Fig. 2a) (Ghaoui et al. 2016). Given the position of this mutation, one can speculate that both LAP1 isoforms (LAP1B and LAP1C) are mutated. However, it does not affect LAP1B directly, since it is absent as a consequence of the first mutation. This is not the case for LAP1C which might be expressed and consequently affected by the second mutation. However, these speculative ideas regarding LAP1C expression and mutation are very exciting, but experimental validation is still required.

Functionally Associated LAP1 Interactors

To date LAP1 function remained elusive, despite the huge effort to determine its physiological role. Therefore, the identification of LAP1 interacting proteins and their putative associated functions seems to be a very powerful strategy to unravelling LAP1 functions. In fact, several LAP1 interactors have already been identified, and many functions were ascribed to LAP1. Among the binding partners are torsinA and emerin that have been functionally associated to LAP1, particularly in neurons and skeletal muscle, respectively. Protein phosphatase 1 (PP1) is also a novel LAP1 interacting protein, and LAP1 phosphorylation/dephosphorylation might represent a key regulatory mechanism across the nuclear membrane. We will focus on the following top LAP1 functionally associated proteins: lamins, torsinA, emerin, and PP1 (Fig. 3).
Torsin 1A Interacting Protein 1, Fig. 3

LAP1 interactors and potential functions. LAP1 is normally located in the nuclear envelope, where it interacts with emerin (a) being essential for its normal localization and crucial for striatal muscle maintenance; LAP1 is also associated with chromatin regulation and the maintenance of NE architecture through the interaction with nuclear lamina (b). LAP1 was found to be dephosphorylated by PP1 (c) and is thought to be hyperphosphorylated during mitosis. LAP1 was also described to interact with torsinA (d) acting as a regulator of torsinA ATPase activity which is associated with DYT1 dystonia. Recently, a novel potential function has been described, relating LAP1 to spermatid elongation throughout spermatogenesis (e)


The nuclear lamina is a protein meshwork that lies in the NE and is composed by polymeric lamins that comprises a group of family members of the intermediate filament proteins. It is well accepted that the formation of lamin polymers at the NE is due to the self-association properties of lamins. However, this process may be modulated by lamin-binding proteins of the INM and/or by chromatin (Schirmer and Foisner 2007). LAP1 was one of the first lamina-associated polypeptides described. Moreover, it was shown that LAP1 binds directly to lamin A/C and lamin B (Foisner and Gerace 1993; Maison et al. 1997). In interphase cells LAP1 is located in the INM in association with lamins (directly) and chromosomes (indirectly). The interaction between LAP1 and lamins seems to be important for targeting lamins to the NE and thereby contributing to the maintenance of the NE architecture (Fig. 3b). However, when cells enter mitosis, the NE is disassembled during prometaphase, and LAP1 seems to be redistributed throughout the ER, losing its association with chromosomes and lamins, thereby contributing to the NE breakdown in the early mitotic events and for NE reassembly upon mitosis.


TorsinA, a member of a family of AAA+ proteins (ATPase associated with different cellular activities) localized in the lumen of the ER, interacts with LAP1 (Goodchild and Dauer 2005). A deletion of a single glutamic acid within torsinA is responsible for DYT1 dystonia, a movement disorder characterized by prolonged involuntary twitching movements (Ozelius et al. 1997). Of note, whereas wild-type torsinA is located in ER and perinuclear space, the mutant torsinA is preferentially located in the perinuclear space (Goodchild and Dauer 2004). Further in vivo studies using both torsinA knockout mutant mice and mice with a germline deletion of Tor1aip1 gene revealed neuron-specific nuclear envelope abnormalities suggesting that both proteins are functionally associated in neurons (Goodchild and Dauer 2005; Kim et al. 2010).

Additionally it is known that torsinA is inactive and requires the stimulation of one or two distinctly localizing transmembrane cofactors, LAP1 or LULL1 (luminal domain-like LAP1), that are regulators of torsinA ATPase activity (Zhao et al. 2013). Recently it was shown that LAP1 adopts a partial AAA+ domain fold and co-assembles with torsinA subunits of an active enzyme. These domains comprise a strictly conserved arginine residue that aligns perfectly with a key catalytic arginine found in AAA+ proteins. The latter residue is therefore critical for torsinA ATPase activity (Brown et al. 2014; Sosa et al. 2014). These results confirm both LAP1 and LULL1 as members of the torsin core machinery.

Several lines of evidence suggest that torsinA and LAP1 might have a combined critical role at the NE dynamics (Fig. 3d). Essentially, several hypothetical models of modes of action were pointed out by Laudermilch and Schlieker (2016). Briefly, the recently described nuclear pore-independent vesicle-driven RNA export pathway (budding pathway through the NE) might require the action of both torsin and LAP1. Additionally, torsinA and LAP1 might also mediate the assembly and disassembly of the LINC complex, NE reassembly upon mitosis or upon NE rupture (Laudermilch and Schlieker 2016). These proposed models are extremely interesting and should be further investigated.


Emerin is an INM protein associated with the X-linked form of Emery-Dreifuss muscular dystrophy, which is characterized by progressive skeletal muscle wasting, contractures, and cardiomyopathy (Bione et al. 1994). Several disease-causing mutations in the emerin gene have been identified, and most of them resulted in decreased levels of emerin and its mislocalization in the cytoplasm (Manilal et al. 1998). Emerin was identified as a LAP1 interacting protein upon a screen for identifying novel LAP1-binding proteins (Shin et al. 2013). The interaction of both proteins is mediated by their nucleoplasmic domain, and emerin binds to LAP1 at residues 1–330 (Shin et al. 2013). These authors conditionally deleted LAP1 from mice striated muscle, which lead to the development of profound muscular dystrophy and cardiomyopathy that culminates with premature mice death. Further studies performed by the same authors indicated that LAP1 is essential for normal localization of emerin and A-type lamin complexes in the INM. Taken together these results suggest that LAP1 is a crucial protein for skletal muscle maintenance, probably together with emerin (Fig. 3a). Surprisingly, studies performed with mice lacking emerin presented only few skeletal muscle abnormalities, while emerin loss in humans causes myopathy and cardiomyopathy. Interestingly, the “Turkish” mutation in the gene encoding LAP1 leads to LAP1B absence and consequently to a form of muscular dystrophy. The same seems to occur with the “Australian” mutation. Together, these studies strengthen the hypothesis that the complex LAP1/emerin is functionally associated in skeletal muscle. It would be particularly interesting to determine whether the two human LAP1 isoforms (LAP1B and LAP1C) are differently expressed in specific pathological conditions, since one can deduce that LAP1C also binds to emerin (Rebelo et al. 2015a).

Protein Phosphatase 1

It was recently reported that LAP1B binds to PP1 (Santos et al. 2013). PP1 is the major eukaryotic serine/threonine phosphatase, and it is estimated that it dephosphorylates around one third of all eukaryotic proteins. PP1 is involved in many cellular processes, and these are dictated by the interaction of the PP1 catalytic subunit with different regulatory subunits. More than 200 PP1 interacting/regulatory proteins have been described. The interaction between LAP1 and PP1 was mapped in the nucleoplasmic domain, and it was determined that LAP1 is a PP1 substrate (Fig. 3c) (Rebelo et al. 2015b; Santos et al. 2013). However, the physiological relevance of this has yet to be determined. Additionally, five different LAP1 phosphorylated residues were identified: Ser143, Ser216, Thr221, Ser306, and Ser310. From those, it was possible to determine that PP1 is able to dephosphorylate Ser306 and Ser310 (Santos et al. 2014). Recent studies also indicate that LAP1 is highly phosphorylated during mitosis (Fig. 3c) (Santos et al. 2015), and given the importance of PP1 during the cell cycle, the physiological relevance and association of these two proteins deserve further elucidation. In particular, the hypothesis that LAP1 phosphorylation might represent a key regulatory mechanism across the nuclear membrane is extremely attractive from a functional perspective at a molecular level.

Novel Functionally Relevant Putative LAP1 Interactors

Functionally relevant putative LAP1 interactors are emerging and will be discussed in this section. The identification of novel LAP1 interacting proteins and their associated cellular functions seems a very important strategy to understand the precise physiological roles of LAP1. Recently, the LAP1 interactome was explored and 41 LAP1 interactors were identified. Of note, this bioinformatic study not only reinforces the putative functions already ascribed to LAP1 but importantly novel putative functions that are associated to the novel putative interactors were reported (Serrano et al. 2016a). Briefly, from the analysis of the biological processes associated to the LAP1 interactome, a significant enrichment in the following was observed: regulation of response to DNA damage, nuclear membrane organization, nuclear envelope organization, cell cycle, chaperone-mediated protein folding, nucleus organization, telomere maintenance, cellular component organization, telomere organization, and cellular component disassembly involved in execution phase of apoptosis (Serrano et al. 2016a). From these biological processes, the regulation of response to DNA damage, telomere maintenance, and telomere organization had never before functionally associated to LAP1. LAP1 seems to be associated with the shelterin complex, which is a multiprotein complex with DNA remodeling activity that promotes structural changes of the telomeric DNA protecting chromosomes ends. The shelterin complex is therefore a protective complex which prevents the recognition of telomeres as sites of damage and is composed of six telomere-specific proteins (TRF1, TRF2, POT1, TIN2, TPP1, and TRF2IP1). Of note, disruption of the shelterin complex leads to activation of DNA damage, a response that includes H2A.X (histone 2A family member) and ATM (ataxia telangiectasia mutated) phosphorylation (Arnoult and Karlseder 2015; de Lange 2005). Given the emerging functions of LAP1 and the identification of novel putative binding partners, TRF2, TRF2IP1, RIF1, and ATM, the hypothesis that LAP1 might have a role in assembly or stabilizing some of the proteins of the shelterin complex is very attractive. Further, bioinformatic studies using the Ingenuity Pathways Analysis tool also strengthened this hypothesis. Interestingly, two canonical pathways associated with the LAP1 interactome were identified: telomerase signaling and telomere extension by telomerase (Serrano et al. 2016a).

Previous studies suggested a putative function for LAP1 related with the cell cycle. Remarkably, in the bioinformatic study of the LAP1 interactome, the cell cycle was in the top three biological processes identified. Neumann et al. reported that LAP1 might have a role in the assembly of mitotic microtubule spindle and consequently in mitosis progression, since the knockdown of LAP1 caused impaired microtubule spindle formation during prometaphase that culminates with aberrant mitotic exit (Neumann et al. 2010). Additionally, LAP1 co-localizes with acetylated α-tubulin in the mitotic spindle and with γ-tubulin in centrosomes (main microtubules organizing center) in mitotic cells. The knockdown of LAP1 results in a decreasing number of mitotic cells, and the positioning of the centrosome near the NE was also altered (Santos et al. 2015). Moreover, the association between MAD2L1 and MAD2L1BP occurs in the mitotic checkpoint complex (MCC). Both proteins also bind to LAP1 and MAD1L1 (Hutchins et al. 2010). Interestingly, the MCC inhibits the anaphase-promoting complex/cyclosome (APC/C), an ubiquitin E3 ligase that promotes chromosome segregation. This inhibition regulates the spindle assembly checkpoint (SAC) that is responsible for the inhibition of chromosome segregation until all sister chromatids achieve bipolar attachment to the mitotic spindle. All together these studies place LAP1 as a key protein in the regulation of cell cycle progression and functionally associated to the MCC.

Another recently described LAP1 function is related with spermatogenesis. We recently determined that LAP1 is expressed during nuclear elongation in spermiogenesis, and it is located at the centriolar pole of spermatids (Fig. 3e). LAP1 is also identified as a novel crucial element for manchette development and a new chromatin regulator via lamin interaction. Overall, by moving to the posterior pole, LAP1 can contribute to the achievement of nonrandom, sperm-specific chromatin distribution and can modulate cellular remodeling during spermiogenesis (Serrano et al. 2016b).


Lamina-associated polypeptide 1 (LAP1) is a type II transmembrane protein of the inner nuclear membrane encoded by the TOR1AIP1 gene. Three LAP1 isoforms have been reported in rat, as a result of alternative splicing. However, in humans only two isoforms were reported, namely, LAP1B and LAP1C, both being abundant in human cells and tissues. Their specific function and mode of action are unknown and deserve further investigation. Several LAP1 binding partners have been asserted; hence some functions have been ascribed to LAP1. These binding partners include lamins, torsinA, emerin, and protein phosphatase 1; and together they accomplish crucial cellular functions, namely, nuclear architecture maintenance and chromatin regulation (LAP1-lamins), regulation of torsinA ATPase activity, nuclear envelope localization of torsinA and NE dynamics (LAP1-torsinA), nuclear envelope integrity maintenance and skeletal muscle maintenance (LAP1-emerin), and regulation of cell cycle progression (LAP1-PP1). Recently four mutations in TOR1AIP1 gene were identified and correspond to the “Turkish” mutation, “Moroccan” mutation, and “Australian” mutation, the latter consists of two different mutations. This new data increases the number of genes associated with nuclear envelopathies and strengthens the hypothesis of LAP1 as a key protein for skeletal and cardiac muscle function and also brain function.


  1. Arnoult N, Karlseder J. Complex interactions between the DNA-damage response and mammalian telomeres. Nat Struct Mol Biol. 2015;22:859–66.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet. 1994;8:323–7.PubMedCrossRefGoogle Scholar
  3. Brown RS, Zhao C, Chase AR, Wang J, Schlieker C. The mechanism of Torsin ATPase activation. Proc Natl Acad Sci USA. 2014;111:E4822–31.PubMedPubMedCentralCrossRefGoogle Scholar
  4. de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev. 2005;19:2100–10.PubMedCrossRefGoogle Scholar
  5. Dorboz I, Coutelier M, Bertrand AT, Caberg JH, Elmaleh-Berges M, Laine J, Stevanin G, Bonne G, Boespflug-Tanguy O, Servais L. Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1. Orphanet J Rare Dis. 2014;9:174.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Foisner R, Gerace L. Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell. 1993;73:1267–79.PubMedCrossRefGoogle Scholar
  7. Ghaoui R, Benavides T, Lek M, Waddell LB, Kaur S, North KN, MacArthur DG, Clarke NF, Cooper ST. TOR1AIP1 as a cause of cardiac failure and recessive limb-girdle muscular dystrophy. Neuromuscul Disord. 2016;26:500–3.PubMedCrossRefGoogle Scholar
  8. Goodchild RE, Dauer WT. Mislocalization to the nuclear envelope: an effect of the dystonia-causing torsinA mutation. Proc Natl Acad Sci USA. 2004;101:847–52.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Goodchild RE, Dauer WT. The AAA+ protein torsinA interacts with a conserved domain present in LAP1 and a novel ER protein. J Cell Biol. 2005;168:855–62.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Hutchins JR, Toyoda Y, Hegemann B, Poser I, Heriche JK, Sykora MM, Augsburg M, Hudecz O, Buschhorn BA, Bulkescher J, Conrad C, Comartin D, Schleiffer A, Sarov M, Pozniakovsky A, Slabicki MM, Schloissnig S, Steinmacher I, Leuschner M, Ssykor A, Lawo S, Pelletier L, Stark H, Nasmyth K, Ellenberg J, Durbin R, Buchholz F, Mechtler K, Hyman AA, Peters JM. Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science. 2010;328:593–9.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Kayman-Kurekci G, Talim B, Korkusuz P, Sayar N, Sarioglu T, Oncel I, Sharafi P, Gundesli H, Balci-Hayta B, Purali N, Serdaroglu-Oflazer P, Topaloglu H, Dincer P. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies. Neuromuscul Disord. 2014;24:624–33.PubMedCrossRefGoogle Scholar
  12. Kim CE, Perez A, Perkins G, Ellisman MH, Dauer WT. A molecular mechanism underlying the neural-specific defect in torsinA mutant mice. Proc Natl Acad Sci USA. 2010;107:9861–6.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Kondo Y, Kondoh J, Hayashi D, Ban T, Takagi M, Kamei Y, Tsuji L, Kim J, Yoneda Y. Molecular cloning of one isotype of human lamina-associated polypeptide 1s and a topological analysis using its deletion mutants. Biochem Biophys Res Commun. 2002;294:770–8.PubMedCrossRefGoogle Scholar
  14. Laudermilch E, Schlieker C. Torsin ATPases: structural insights and functional perspectives. Curr Opin Cell Biol. 2016;40:1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Maison C, Pyrpasopoulou A, Theodoropoulos PA, Georgatos SD. The inner nuclear membrane protein LAP1 forms a native complex with B-type lamins and partitions with spindle-associated mitotic vesicles. EMBO J. 1997;16:4839–50.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Manilal S, Recan D, Sewry CA, Hoeltzenbein M, Llense S, Leturcq F, Deburgrave N, Barbot J, Man N, Muntoni F, Wehnert M, Kaplan J, Morris GE. Mutations in Emery-Dreifuss muscular dystrophy and their effects on emerin protein expression. Hum Mol Genet. 1998;7:855–64.PubMedCrossRefGoogle Scholar
  17. Martin L, Crimaudo C, Gerace L. cDNA cloning and characterization of lamina-associated polypeptide 1C (LAP1C), an integral protein of the inner nuclear membrane. J Biol Chem. 1995;270:8822–8.PubMedCrossRefGoogle Scholar
  18. Neumann B, Walter T, Heriche JK, Bulkescher J, Erfle H, Conrad C, Rogers P, Poser I, Held M, Liebel U, Cetin C, Sieckmann F, Pau G, Kabbe R, Wunsche A, Satagopam V, Schmitz MH, Chapuis C, Gerlich DW, Schneider R, Eils R, Huber W, Peters JM, Hyman AA, Durbin R, Pepperkok R, Ellenberg J. Phenotypic profiling of the human genome by time-lapse microscopy reveals cell division genes. Nature. 2010;464:721–7.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Ozelius LJ, Hewett JW, Page CE, Bressman SB, Kramer PL, Shalish C, de Leon D, Brin MF, Raymond D, Corey DP, Fahn S, Risch NJ, Buckler AJ, Gusella JF, Breakefield XO. The early-onset torsion dystonia gene (DYT1) encodes an ATP-binding protein. Nat Genet. 1997;17:40–8.PubMedCrossRefGoogle Scholar
  20. Rebelo S, da Cruz ESEF, da Cruz ESOA. Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy. Mutat Res Rev Mutat Res. 2015a;766:42–7.PubMedCrossRefGoogle Scholar
  21. Rebelo S, Santos M, Martins F, da Cruz ESEF, da Cruz ESOA. Protein phosphatase 1 is a key player in nuclear events. Cell Signal. 2015b;27:2589–98.PubMedCrossRefGoogle Scholar
  22. Santos M, Rebelo S, Van Kleeff PJ, Kim CE, Dauer WT, Fardilha M, da Cruz ESOA, da Cruz ESEF. The nuclear envelope protein, LAP1B, is a novel protein phosphatase 1 substrate. Plos One. 2013;8:e76788.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Santos M, Domingues SC, Costa P, Muller T, Galozzi S, Marcus K, da Cruz ESEF, da Cruz ESOA, Rebelo S. Identification of a novel human LAP1 Isoform that is regulated by protein phosphorylation. Plos One. 2014;9:e113732.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Santos M, Costa P, Martins F, da Cruz e Silva EF, da Cruz e Silva OA, Rebelo S. LAP1 is a crucial protein for the maintenance of the nuclear envelope structure and cell cycle progression. Mol Cell Biochem. 2015;399:143–153.Google Scholar
  25. Schirmer EC, Foisner R. Proteins that associate with lamins: many faces, many functions. Exp Cell Res. 2007;313:2167–79.PubMedCrossRefGoogle Scholar
  26. Senior A, Gerace L. Integral membrane proteins specific to the inner nuclear membrane and associated with the nuclear lamina. J Cell Biol. 1988;107:2029–36.PubMedCrossRefGoogle Scholar
  27. Serrano JB, da Cruz ESOA, Rebelo S. Lamina associated polypeptide 1 (LAP1) interactome and its functional features. Membranes (Basel). 2016a;6. doi:10.3390/membranes6010008.Google Scholar
  28. Serrano JB, Martins F, Sousa JC, van Pelt AMM, Rebelo S, da Cruz e Silva OAB. The distribution of LAP1 and associated proteins throughout spermatogenesis. Reprod Fertil Dev (submitted). 2016b.Google Scholar
  29. Shin JY, Mendez-Lopez I, Wang Y, Hays AP, Tanji K, Lefkowitch JH, Schulze PC, Worman HJ, Dauer WT. Lamina-associated polypeptide-1 interacts with the muscular dystrophy protein emerin and is essential for skeletal muscle maintenance. Dev Cell. 2013;26:591–603.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Sosa BA, Demircioglu FE, Chen JZ, Ingram J, Ploegh HL, Schwartz TU. How lamina-associated polypeptide 1 (LAP1) activates Torsin. Elife. 2014;3:e03239.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Tadokoro K, Yamazaki-Inoue M, Tachibana M, Fujishiro M, Nagao K, Toyoda M, Ozaki M, Ono M, Miki N, Miyashita T, Yamada M. Frequent occurrence of protein isoforms with or without a single amino acid residue by subtle alternative splicing: the case of Gln in DRPLA affects subcellular localization of the products. J Hum Genet. 2005;50:382–94.PubMedCrossRefGoogle Scholar
  32. Zhao C, Brown RS, Chase AR, Eisele MR, Schlieker C. Regulation of Torsin ATPases by LAP1 and LULL1. Proc Natl Acad Sci USA. 2013;110:E1545–54.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Joana B. Serrano
    • 1
  • Filipa Martins
    • 1
  • Ana M. Marafona
    • 1
  • Odete A. B. da Cruz e Silva
    • 1
  • Sandra Rebelo
    • 1
  1. 1.Neuroscience and Signaling Laboratory, Department of Medical Sciences, Institute of Biomedicine-iBiMEDUniversity of AveiroAveiroPortugal