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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''VAMP-Associated Protein A''' ( or [[Vesicle-associated membrane protein|Vesicle-Associated Membrane Protein]]-Associated Protein A) is a [[protein]] that in humans is encoded by the ''VAPA'' [[gene]].<ref name="pmid9920726">{{cite journal | vauthors = Nishimura Y, Hayashi M, Inada H, Tanaka T | title = Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins | journal = Biochemical and Biophysical Research Communications | volume = 254 | issue = 1 | pages = 21–6 | date = January 1999 | pmid = 9920726 | pmc =  | doi = 10.1006/bbrc.1998.9876 }}</ref><ref name="pmid9657962">{{cite journal | vauthors = Weir ML, Klip A, Trimble WS | title = Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP | journal = The Biochemical Journal | volume = 333 ( Pt 2) | issue = 2 | pages = 247–51 | date = July 1998 | pmid = 9657962 | pmc = 1219579 | doi = 10.1042/bj3330247 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: VAPA VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9218| access-date = }}</ref> Together with [[VAPB]] and VAPC it forms the [[VAP protein family]]. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes.<ref name=":1" />
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
VAPA is ubiquitously expressed in human tissues<ref name="pmid9920726" /> and is thought to be involved in membrane trafficking by interaction with [[SNARE (protein)|SNARE]]s.<ref name=":0">{{cite journal | vauthors = Weir ML, Xie H, Klip A, Trimble WS | title = VAP-A binds promiscuously to both v- and tSNAREs | journal = Biochemical and Biophysical Research Communications | volume = 286 | issue = 3 | pages = 616–21 | date = August 2001 | pmid = 11511104 | doi = 10.1006/bbrc.2001.5437 }}</ref> in regulation of lipid transport and metabolism,<ref name=":1">{{cite journal | vauthors = Lev S, Ben Halevy D, Peretti D, Dahan N | title = The VAP protein family: from cellular functions to motor neuron disease | journal = Trends in Cell Biology | volume = 18 | issue = 6 | pages = 282–90 | date = June 2008 | pmid = 18468439 | doi = 10.1016/j.tcb.2008.03.006 }}</ref> and in the Unfolded Protein Response ([[Unfolded protein response|UPR]]).<ref name=":1" />
{{GNF_Protein_box
| image = PBB_Protein_VAPA_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1z9l.
| PDB = {{PDB2|1z9l}}, {{PDB2|1z9o}}, {{PDB2|2cri}}
| Name = VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa
| HGNCid = 12648
| Symbol = VAPA
| AltSymbols =; MGC3745; VAP-33; VAP-A; VAP33; hVAP-33
| OMIM = 605703
| ECnumber =
| Homologene = 37824
| MGIid = 1353561
| GeneAtlas_image1 = PBB_GE_VAPA_208780_x_at_tn.png
| Function = {{GNF_GO|id=GO:0004871 |text = signal transducer activity}} {{GNF_GO|id=GO:0005198 |text = structural molecule activity}}
| Component = {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006461 |text = protein complex assembly}} {{GNF_GO|id=GO:0006887 |text = exocytosis}} {{GNF_GO|id=GO:0006944 |text = membrane fusion}} {{GNF_GO|id=GO:0043123 |text = positive regulation of I-kappaB kinase/NF-kappaB cascade}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9218
    | Hs_Ensembl = ENSG00000101558
    | Hs_RefseqProtein = NP_003565
    | Hs_RefseqmRNA = NM_003574
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 18
    | Hs_GenLoc_start = 9903984
    | Hs_GenLoc_end = 9949571
    | Hs_Uniprot = Q9P0L0
    | Mm_EntrezGene = 30960
    | Mm_Ensembl = ENSMUSG00000024091
    | Mm_RefseqmRNA = NM_013933
    | Mm_RefseqProtein = NP_038961
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 17
    | Mm_GenLoc_start = 65479596
    | Mm_GenLoc_end = 65513084
    | Mm_Uniprot = Q9WV55
  }}
}}
'''VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa''', also known as '''VAPA''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: VAPA VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9218| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{PBB_Summary
| section_title =
| summary_text = The protein encoded by this gene is a type IV membrane protein. It is present in the plasma membrane and intracellular vesicles. It may also be associated with the cytoskeleton. This protein may function in vesicle trafficking, membrane fusion, protein complex assembly and cell motility. Alternative splicing occurs at this locus and two transcript variants encoding distinct isoforms have been identified.<ref name="entrez">{{cite web | title = Entrez Gene: VAPA VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9218| accessdate = }}</ref>
}}


==References==
 
{{reflist|2}}
==Protein structure==
==Further reading==
 
The protein is divided in three different domains.<ref name="pmid9920726" /> First, an N-terminal  [[Beta sheet|beta-sheet]] with an immunoglobulin-like fold that shares homology with the Nematode major sperm protein ([[Major sperm protein|MSP]]). Secondly, a central [[Coiled coil|coiled-coil]] domain. Then finally a C-terminal [[transmembrane domain]] (TMD) which is usually present in proteins of the [[t-SNARE]] superfamily and has been found in other proteins associated with vesicular transport.<ref>{{cite journal | vauthors = Weimbs T, Low SH, Chapin SJ, Mostov KE, Bucher P, Hofmann K | title = A conserved domain is present in different families of vesicular fusion proteins: a new superfamily | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 7 | pages = 3046–51 | date = April 1997 | pmid = 9096343 | pmc = 20319 }}</ref> VAPA can form homo-dimers and also hetero dimers with VAPB by interactions through their (TMD).<ref name="pmid9920726" />
 
==Intracellular Localisation==
 
Because of its ubiquitous expression<ref name="pmid9920726" />, the intracellular localisation and function of VAPA may vary between cell types. It is however mainly located in the ER<ref>{{cite journal | vauthors = Skehel PA, Fabian-Fine R, Kandel ER | title = Mouse VAP33 is associated with the endoplasmic reticulum and microtubules | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 3 | pages = 1101–6 | date = February 2000 | pmid = 10655491 | pmc = 15535 }}</ref>, Golgi apparatus and the [[ERGIC|Vesicular Tubular Compartment or ER-Golgi Intermediate Compartment]],<ref name=":0" /> an organelle of eukaryotic cells consisting in fused ER-derived vesicles that transports proteins from the ER to the Golgi apparatus.<ref>{{cite journal | vauthors = Appenzeller-Herzog C, Hauri HP | title = The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function | journal = Journal of Cell Science | volume = 119 | issue = Pt 11 | pages = 2173–83 | date = June 2006 | pmid = 16723730 | doi = 10.1242/jcs.03019 }}</ref>
 
== Interactions ==
 
VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing the [[FFAT motif]] and viral proteins.<ref name=":1" />
===Vesicle traffic and fusion===
VAPA is able to bind a range of SNARE proteins including [[STX1A|syntaxin1A]], rbet1 and rsec22. It also binds to proteins associated with membrane fusion machinery such as alphaSNAP and [[NSFL1C|NSF]].These interaction suggest that VAPA could have a general role in the regulation of the function of these proteins that are mainly involved in membrane fusion<ref name=":0" />
 
===Viral Proteins===
VAP proteins have been found to be essential host factors for several viruses.<ref name=":2">{{cite journal | vauthors = Ettayebi K, Hardy ME | title = Norwalk virus nonstructural protein p48 forms a complex with the SNARE regulator VAP-A and prevents cell surface expression of vesicular stomatitis virus G protein | journal = Journal of Virology | volume = 77 | issue = 21 | pages = 11790–7 | date = November 2003 | pmid = 14557663 | pmc = 229264 | doi = 10.1128/JVI.77.21.11790-11797.2003 }}</ref><ref name=":3">{{cite journal | vauthors = McCune BT, Tang W, Lu J, Eaglesham JB, Thorne L, Mayer AE, Condiff E, Nice TJ, Goodfellow I, Krezel AM, Virgin HW | title = Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine-Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2 | journal = mBio | volume = 8 | issue = 4 | pages = e00668–17 | date = July 2017 | pmid = 28698274 | pmc = 5513711 | doi = 10.1128/mBio.00668-17 }}</ref><ref>{{cite journal | vauthors = Ishikawa-Sasaki K, Nagashima S, Taniguchi K, Sasaki J | title = Model of OSBP-Mediated Cholesterol Supply to Aichi Virus RNA Replication Sites Involving Protein-Protein Interactions among Viral Proteins, ACBD3, OSBP, VAP-A/B, and SAC1 | journal = Journal of Virology | volume = 92 | issue = 8 | pages = e01952–17 | date = April 2018 | pmid = 29367253 | pmc = 5874406 | doi = 10.1128/JVI.01952-17 }}</ref>
 
VAP proteins binds with non-structural proteins of the hepatitis C virus [[NS5A]] and [[NS5B]] allowing the RNA replication machinery of the virus to set up on the [[lipid raft]] membrane of the host cell.<ref>{{cite journal | vauthors = Gao L, Aizaki H, He JW, Lai MM | title = Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft | journal = Journal of Virology | volume = 78 | issue = 7 | pages = 3480–8 | date = April 2004 | pmid = 15016871 | pmc = 371042 | doi = 10.1128/JVI.78.7.3480-3488.2004 }}</ref>
 
VAPA also binds to several viral proteins from the [[Norovirus]] family and is important for the virus replication efficiency.<ref name=":2" /><ref name=":3" /> The non-structural proteins NS1 and NS2 are able to bind VAPA thanks to sequence mimicry of the FFAT motif probably yielding the same advantage to viral replication as for hepatitis C virus.<ref name=":3" />
 
===FFAT motif===
The N-terminal MSP-homologous part of VAPA is able to bind to the [[FFAT motif|FFAT]] motif, a particular sequence motif shared by several lipid binding proteins including oxysterol-binding protein ([[Oxysterol-binding protein|OSBP]]).<ref>{{cite journal | vauthors = Wyles JP, McMaster CR, Ridgway ND | title = Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 277 | issue = 33 | pages = 29908–18 | date = August 2002 | pmid = 12023275 | doi = 10.1074/jbc.M201191200 }}</ref><ref>{{cite journal | vauthors = Wyles JP, Ridgway ND | title = VAMP-associated protein-A regulates partitioning of oxysterol-binding protein-related protein-9 between the endoplasmic reticulum and Golgi apparatus | journal = Experimental Cell Research | volume = 297 | issue = 2 | pages = 533–47 | date = July 2004 | pmid = 15212954 | doi = 10.1016/j.yexcr.2004.03.052 }}</ref>
 
== Function ==
One of its proposed functions is to slow down the lipid flow back towards the ER when protein misfolding occurs, in order to reduce the amount of stress triggered by the UPR. The VAP would regulate this process by inhibiting membrane contact.<ref name=":4">{{cite journal | vauthors = Ernst WL, Shome K, Wu CC, Gong X, Frizzell RA, Aridor M | title = VAMP-associated Proteins (VAP) as Receptors That Couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Proteostasis with Lipid Homeostasis | journal = The Journal of Biological Chemistry | volume = 291 | issue = 10 | pages = 5206–20 | date = March 2016 | pmid = 26740627 | pmc = 4777854 | doi = 10.1074/jbc.M115.692749  }}</ref>
 
==Associated Diseases==
 
 The P56S SNP in the MSP domain of VAPB is involved in the onset of Lou Gehrig's disease also called amyotrophic lateral sclerosis ([[ALS]]) where the patient loses muscle control and function. The degenerescence of motor neurons observed in such condition could to be due to the inability of VAPB to regulate the lipid function around the ER and the subsequent consequences on cell function.<ref name=":4" />
 
== References ==
{{reflist}}
 
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Lapierre LA, Tuma PL, Navarre J, Goldenring JR, Anderson JM | title = VAP-33 localizes to both an intracellular vesicle population and with occludin at the tight junction | journal = Journal of Cell Science | volume = 112 ( Pt 21) | issue = 21 | pages = 3723–32 | date = November 1999 | pmid = 10523508 | doi =  }}
| citations =
* {{cite journal | vauthors = Tu H, Gao L, Shi ST, Taylor DR, Yang T, Mircheff AK, Wen Y, Gorbalenya AE, Hwang SB, Lai MM | title = Hepatitis C virus RNA polymerase and NS5A complex with a SNARE-like protein | journal = Virology | volume = 263 | issue = 1 | pages = 30–41 | date = October 1999 | pmid = 10544080 | doi = 10.1006/viro.1999.9893 }}
*{{cite journal  | author=Weir ML, Klip A, Trimble WS |title=Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP. |journal=Biochem. J. |volume=333 ( Pt 2) |issue=  |pages= 247-51 |year= 1998 |pmid= 9657962 |doi=  }}
* {{cite journal | vauthors = Weir ML, Xie H, Klip A, Trimble WS | title = VAP-A binds promiscuously to both v- and tSNAREs | journal = Biochemical and Biophysical Research Communications | volume = 286 | issue = 3 | pages = 616–21 | date = August 2001 | pmid = 11511104 | doi = 10.1006/bbrc.2001.5437 }}
*{{cite journal  | author=Nishimura Y, Hayashi M, Inada H, Tanaka T |title=Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins. |journal=Biochem. Biophys. Res. Commun. |volume=254 |issue= 1 |pages= 21-6 |year= 1999 |pmid= 9920726 |doi= 10.1006/bbrc.1998.9876 }}
* {{cite journal | vauthors = Wyles JP, McMaster CR, Ridgway ND | title = Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum | journal = The Journal of Biological Chemistry | volume = 277 | issue = 33 | pages = 29908–18 | date = August 2002 | pmid = 12023275 | doi = 10.1074/jbc.M201191200 }}
*{{cite journal | author=Lapierre LA, Tuma PL, Navarre J, ''et al.'' |title=VAP-33 localizes to both an intracellular vesicle population and with occludin at the tight junction. |journal=J. Cell. Sci. |volume=112 ( Pt 21) |issue= |pages= 3723-32 |year= 1999 |pmid= 10523508 |doi=  }}
* {{cite journal | vauthors = Matsuda A, Suzuki Y, Honda G, Muramatsu S, Matsuzaki O, Nagano Y, Doi T, Shimotohno K, Harada T, Nishida E, Hayashi H, Sugano S | title = Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways | journal = Oncogene | volume = 22 | issue = 21 | pages = 3307–18 | date = May 2003 | pmid = 12761501 | doi = 10.1038/sj.onc.1206406 }}
*{{cite journal | author=Tu H, Gao L, Shi ST, ''et al.'' |title=Hepatitis C virus RNA polymerase and NS5A complex with a SNARE-like protein. |journal=Virology |volume=263 |issue= 1 |pages= 30-41 |year= 1999 |pmid= 10544080 |doi= 10.1006/viro.1999.9893 }}
* {{cite journal | vauthors = Gao L, Aizaki H, He JW, Lai MM | title = Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft | journal = Journal of Virology | volume = 78 | issue = 7 | pages = 3480–8 | date = April 2004 | pmid = 15016871 | pmc = 371042 | doi = 10.1128/JVI.78.7.3480-3488.2004 }}
*{{cite journal | author=Weir ML, Xie H, Klip A, Trimble WS |title=VAP-A binds promiscuously to both v- and tSNAREs. |journal=Biochem. Biophys. Res. Commun. |volume=286 |issue= 3 |pages= 616-21 |year= 2001 |pmid= 11511104 |doi= 10.1006/bbrc.2001.5437 }}
* {{cite journal | vauthors = Evans MJ, Rice CM, Goff SP | title = Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 35 | pages = 13038–43 | date = August 2004 | pmid = 15326295 | pmc = 516513 | doi = 10.1073/pnas.0405152101 | bibcode = 2004PNAS..10113038E }}
*{{cite journal | author=Wyles JP, McMaster CR, Ridgway ND |title=Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum. |journal=J. Biol. Chem. |volume=277 |issue= 33 |pages= 29908-18 |year= 2002 |pmid= 12023275 |doi= 10.1074/jbc.M201191200 }}
* {{cite journal | vauthors = Suzuki Y, Yamashita R, Shirota M, Sakakibara Y, Chiba J, Mizushima-Sugano J, Nakai K, Sugano S | title = Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions | journal = Genome Research | volume = 14 | issue = 9 | pages = 1711–8 | date = September 2004 | pmid = 15342556 | pmc = 515316 | doi = 10.1101/gr.2435604 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R }}
*{{cite journal  | author=Matsuda A, Suzuki Y, Honda G, ''et al.'' |title=Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways. |journal=Oncogene |volume=22 |issue= 21 |pages= 3307-18 |year= 2003 |pmid= 12761501 |doi= 10.1038/sj.onc.1206406 }}
* {{cite journal | vauthors = Hamamoto I, Nishimura Y, Okamoto T, Aizaki H, Liu M, Mori Y, Abe T, Suzuki T, Lai MM, Miyamura T, Moriishi K, Matsuura Y | title = Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B | journal = Journal of Virology | volume = 79 | issue = 21 | pages = 13473–82 | date = November 2005 | pmid = 16227268 | pmc = 1262604 | doi = 10.1128/JVI.79.21.13473-13482.2005 }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
* {{cite journal | vauthors = Kawano M, Kumagai K, Nishijima M, Hanada K | title = Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT | journal = The Journal of Biological Chemistry | volume = 281 | issue = 40 | pages = 30279–88 | date = October 2006 | pmid = 16895911 | doi = 10.1074/jbc.M605032200 }}
*{{cite journal  | author=Gao L, Aizaki H, He JW, Lai MM |title=Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. |journal=J. Virol. |volume=78 |issue= 7 |pages= 3480-8 |year= 2004 |pmid= 15016871 |doi= }}
*{{cite journal | author=Evans MJ, Rice CM, Goff SP |title=Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue= 35 |pages= 13038-43 |year= 2004 |pmid= 15326295 |doi= 10.1073/pnas.0405152101 }}
*{{cite journal | author=Suzuki Y, Yamashita R, Shirota M, ''et al.'' |title=Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. |journal=Genome Res. |volume=14 |issue= 9 |pages= 1711-8 |year= 2004 |pmid= 15342556 |doi= 10.1101/gr.2435604 }}
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
*{{cite journal | author=Hamamoto I, Nishimura Y, Okamoto T, ''et al.'' |title=Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. |journal=J. Virol. |volume=79 |issue= 21 |pages= 13473-82 |year= 2005 |pmid= 16227268 |doi= 10.1128/JVI.79.21.13473-13482.2005 }}
*{{cite journal | author=Kawano M, Kumagai K, Nishijima M, Hanada K |title=Efficient trafficking of ceramide from the endoplasmic reticulum to the Golgi apparatus requires a VAMP-associated protein-interacting FFAT motif of CERT. |journal=J. Biol. Chem. |volume=281 |issue= 40 |pages= 30279-88 |year= 2006 |pmid= 16895911 |doi= 10.1074/jbc.M605032200 }}
}}
{{refend}}
{{refend}}
{{PDB Gallery|geneid=9218}}


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Latest revision as of 09:03, 9 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ensembl

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UniProt

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RefSeq (mRNA)

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VAMP-Associated Protein A ( or Vesicle-Associated Membrane Protein-Associated Protein A) is a protein that in humans is encoded by the VAPA gene.[1][2][3] Together with VAPB and VAPC it forms the VAP protein family. They are integral endoplasmic reticulum membrane proteins of the type II and are ubiquitous among eukaryotes.[4]

VAPA is ubiquitously expressed in human tissues[1] and is thought to be involved in membrane trafficking by interaction with SNAREs.[5] in regulation of lipid transport and metabolism,[4] and in the Unfolded Protein Response (UPR).[4]


Protein structure

The protein is divided in three different domains.[1] First, an N-terminal beta-sheet with an immunoglobulin-like fold that shares homology with the Nematode major sperm protein (MSP). Secondly, a central coiled-coil domain. Then finally a C-terminal transmembrane domain (TMD) which is usually present in proteins of the t-SNARE superfamily and has been found in other proteins associated with vesicular transport.[6] VAPA can form homo-dimers and also hetero dimers with VAPB by interactions through their (TMD).[1]

Intracellular Localisation

Because of its ubiquitous expression[1], the intracellular localisation and function of VAPA may vary between cell types. It is however mainly located in the ER[7], Golgi apparatus and the Vesicular Tubular Compartment or ER-Golgi Intermediate Compartment,[5] an organelle of eukaryotic cells consisting in fused ER-derived vesicles that transports proteins from the ER to the Golgi apparatus.[8]

Interactions

VAPA has been documented to interact with three different groups of proteins: proteins associated with vesicle traffic and fusion, proteins containing the FFAT motif and viral proteins.[4]

Vesicle traffic and fusion

VAPA is able to bind a range of SNARE proteins including syntaxin1A, rbet1 and rsec22. It also binds to proteins associated with membrane fusion machinery such as alphaSNAP and NSF.These interaction suggest that VAPA could have a general role in the regulation of the function of these proteins that are mainly involved in membrane fusion[5]

Viral Proteins

VAP proteins have been found to be essential host factors for several viruses.[9][10][11]

VAP proteins binds with non-structural proteins of the hepatitis C virus NS5A and NS5B allowing the RNA replication machinery of the virus to set up on the lipid raft membrane of the host cell.[12]

VAPA also binds to several viral proteins from the Norovirus family and is important for the virus replication efficiency.[9][10] The non-structural proteins NS1 and NS2 are able to bind VAPA thanks to sequence mimicry of the FFAT motif probably yielding the same advantage to viral replication as for hepatitis C virus.[10]

FFAT motif

The N-terminal MSP-homologous part of VAPA is able to bind to the FFAT motif, a particular sequence motif shared by several lipid binding proteins including oxysterol-binding protein (OSBP).[13][14]

Function

One of its proposed functions is to slow down the lipid flow back towards the ER when protein misfolding occurs, in order to reduce the amount of stress triggered by the UPR. The VAP would regulate this process by inhibiting membrane contact.[15]

Associated Diseases

 The P56S SNP in the MSP domain of VAPB is involved in the onset of Lou Gehrig's disease also called amyotrophic lateral sclerosis (ALS) where the patient loses muscle control and function. The degenerescence of motor neurons observed in such condition could to be due to the inability of VAPB to regulate the lipid function around the ER and the subsequent consequences on cell function.[15]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Nishimura Y, Hayashi M, Inada H, Tanaka T (January 1999). "Molecular cloning and characterization of mammalian homologues of vesicle-associated membrane protein-associated (VAMP-associated) proteins". Biochemical and Biophysical Research Communications. 254 (1): 21–6. doi:10.1006/bbrc.1998.9876. PMID 9920726.
  2. ↑ Weir ML, Klip A, Trimble WS (July 1998). "Identification of a human homologue of the vesicle-associated membrane protein (VAMP)-associated protein of 33 kDa (VAP-33): a broadly expressed protein that binds to VAMP". The Biochemical Journal. 333 ( Pt 2) (2): 247–51. doi:10.1042/bj3330247. PMC 1219579. PMID 9657962.
  3. ↑ "Entrez Gene: VAPA VAMP (vesicle-associated membrane protein)-associated protein A, 33kDa".
  4. ↑ 4.0 4.1 4.2 4.3 Lev S, Ben Halevy D, Peretti D, Dahan N (June 2008). "The VAP protein family: from cellular functions to motor neuron disease". Trends in Cell Biology. 18 (6): 282–90. doi:10.1016/j.tcb.2008.03.006. PMID 18468439.
  5. ↑ 5.0 5.1 5.2 Weir ML, Xie H, Klip A, Trimble WS (August 2001). "VAP-A binds promiscuously to both v- and tSNAREs". Biochemical and Biophysical Research Communications. 286 (3): 616–21. doi:10.1006/bbrc.2001.5437. PMID 11511104.
  6. ↑ Weimbs T, Low SH, Chapin SJ, Mostov KE, Bucher P, Hofmann K (April 1997). "A conserved domain is present in different families of vesicular fusion proteins: a new superfamily". Proceedings of the National Academy of Sciences of the United States of America. 94 (7): 3046–51. PMC 20319. PMID 9096343.
  7. ↑ Skehel PA, Fabian-Fine R, Kandel ER (February 2000). "Mouse VAP33 is associated with the endoplasmic reticulum and microtubules". Proceedings of the National Academy of Sciences of the United States of America. 97 (3): 1101–6. PMC 15535. PMID 10655491.
  8. ↑ Appenzeller-Herzog C, Hauri HP (June 2006). "The ER-Golgi intermediate compartment (ERGIC): in search of its identity and function". Journal of Cell Science. 119 (Pt 11): 2173–83. doi:10.1242/jcs.03019. PMID 16723730.
  9. ↑ 9.0 9.1 Ettayebi K, Hardy ME (November 2003). "Norwalk virus nonstructural protein p48 forms a complex with the SNARE regulator VAP-A and prevents cell surface expression of vesicular stomatitis virus G protein". Journal of Virology. 77 (21): 11790–7. doi:10.1128/JVI.77.21.11790-11797.2003. PMC 229264. PMID 14557663.
  10. ↑ 10.0 10.1 10.2 McCune BT, Tang W, Lu J, Eaglesham JB, Thorne L, Mayer AE, Condiff E, Nice TJ, Goodfellow I, Krezel AM, Virgin HW (July 2017). "Noroviruses Co-opt the Function of Host Proteins VAPA and VAPB for Replication via a Phenylalanine-Phenylalanine-Acidic-Tract-Motif Mimic in Nonstructural Viral Protein NS1/2". mBio. 8 (4): e00668–17. doi:10.1128/mBio.00668-17. PMC 5513711. PMID 28698274.
  11. ↑ Ishikawa-Sasaki K, Nagashima S, Taniguchi K, Sasaki J (April 2018). "Model of OSBP-Mediated Cholesterol Supply to Aichi Virus RNA Replication Sites Involving Protein-Protein Interactions among Viral Proteins, ACBD3, OSBP, VAP-A/B, and SAC1". Journal of Virology. 92 (8): e01952–17. doi:10.1128/JVI.01952-17. PMC 5874406. PMID 29367253.
  12. ↑ Gao L, Aizaki H, He JW, Lai MM (April 2004). "Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft". Journal of Virology. 78 (7): 3480–8. doi:10.1128/JVI.78.7.3480-3488.2004. PMC 371042. PMID 15016871.
  13. ↑ Wyles JP, McMaster CR, Ridgway ND (August 2002). "Vesicle-associated membrane protein-associated protein-A (VAP-A) interacts with the oxysterol-binding protein to modify export from the endoplasmic reticulum". The Journal of Biological Chemistry. 277 (33): 29908–18. doi:10.1074/jbc.M201191200. PMID 12023275.
  14. ↑ Wyles JP, Ridgway ND (July 2004). "VAMP-associated protein-A regulates partitioning of oxysterol-binding protein-related protein-9 between the endoplasmic reticulum and Golgi apparatus". Experimental Cell Research. 297 (2): 533–47. doi:10.1016/j.yexcr.2004.03.052. PMID 15212954.
  15. ↑ 15.0 15.1 Ernst WL, Shome K, Wu CC, Gong X, Frizzell RA, Aridor M (March 2016). "VAMP-associated Proteins (VAP) as Receptors That Couple Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Proteostasis with Lipid Homeostasis". The Journal of Biological Chemistry. 291 (10): 5206–20. doi:10.1074/jbc.M115.692749. PMC 4777854. PMID 26740627.

Further reading


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