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VPS26A

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VPS26A
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesVPS26A, HB58, Hbeta58, PEP8A, VPS26, VPS26 retromer complex component A, VPS26, retromer complex component A
External IDsOMIM: 605506; MGI: 1353654; HomoloGene: 68420; GeneCards: VPS26A; OMA:VPS26A - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001035260
NM_004896
NM_001318944
NM_001318945
NM_001318946

NM_001113355
NM_133672
NM_001358543

RefSeq (protein)

NP_001030337
NP_001305873
NP_001305874
NP_001305875
NP_004887

NP_001106826
NP_598433
NP_001345472

Location (UCSC)Chr 10: 69.12 – 69.17 MbChr 10: 62.29 – 62.32 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.[5][6][7]

This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex. Alternative splicing results in multiple transcript variants encoding different isoforms.[7]

Structure

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Structural comparison of Vps26 with arrestins

Vps26 is a 38-kDa subunit that has a two-lobed structure with a polar core that resembles the arrestin family of trafficking adaptor.[8][9] This fold consist of two related β-sandwich subdomains with a fibronectin type III domain topology. The two domains are joined together by a flexible linker and are closely associated by an unusual polar core. Arrestins are regulatory proteins known for connecting G-protein coupled receptors (GPCRs) to clathrin during endocytosis. They play many critical roles in cell signalling and membrane trafficking.[10] Both Vps26 and arrestins are composed of two structurally related β-sheet domains forming extensive interfaces with each other, using polar and electrostatic contacts to create interdomain interactions for ligand binding. However, there are significant structural differences between both Vps26 and arrestins. Vps26 protein has extended C-terminal tails that do not contain identifiable clathrin- or AP2-binding sequences, and therefore cannot form stable intramolecular contacts with clathrin and AP2, which has been observed for arrestins. Moreover, Vps26 does not have similar sequences as arrestins for GPCR and phospholipid interactions.[11]

Vps26B paralogue

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Structural differences between Vps26A and Vps26B

In yeast, there is only one Vps26 species, whereas there are two Vps26 paralogues (Vps26A and Vps26B) in mammals.[12]

X-ray crystallography revealed that the structures of both Vps26A and Vps26B share a similar bilobal β-sandwich structure and possess 70% sequence homology.[8] However, these two paralogues distinctly differ on the surface patch within the N-terminal domain, the apex region where the N-terminal and C-terminal domains meet and the disordered C-terminal tail. Vps26B contains several putative serine phosphorylation residues within this disordered tail, which may represent a potential mechanism to modulate the difference between Vps26A and Vps26B. A recent study conducted by Bugarcic et al. pinpointed that this disordered tail on C-terminal region of Vps26B is one of the underlying factors that contributes to the failure for Vps26B-containing Retromer to associate with CI-M6PR, ultimately leading to CI-M6PR degradation, accompanied with increased cathepsin D secretion.[13]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000122958Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020078Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Lee JJ, Radice G, Perkins CP, Costantini F (Aug 1992). "Identification and characterization of a novel, evolutionarily conserved gene disrupted by the murine H beta 58 embryonic lethal transgene insertion". Development. 115 (1): 277–88. doi:10.1242/dev.115.1.277. PMID 1638986.
  6. ^ Mao M, Fu G, Wu JS, Zhang QH, Zhou J, Kan LX, Huang QH, He KL, Gu BW, Han ZG, Shen Y, Gu J, Yu YP, Xu SH, Wang YX, Chen SJ, Chen Z (Aug 1998). "Identification of genes expressed in human CD34+ hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning". Proc Natl Acad Sci U S A. 95 (14): 8175–80. Bibcode:1998PNAS...95.8175M. doi:10.1073/pnas.95.14.8175. PMC 20949. PMID 9653160.
  7. ^ a b "Entrez Gene: VPS26A vacuolar protein sorting 26 homolog A (S. pombe)".
  8. ^ a b Collins BM, Norwood SJ, Kerr MC, Mahony D, Seaman MN, Teasdale RD, Owen DJ (March 2008). "Structure of Vps26B and mapping of its interaction with the retromer protein complex". Traffic. 9 (3): 366–79. doi:10.1111/j.1600-0854.2007.00688.x. PMID 18088321. S2CID 37113942.
  9. ^ Shi H, Rojas R, Bonifacino JS, Hurley JH (June 2006). "The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain". Nat. Struct. Mol. Biol. 13 (6): 540–8. doi:10.1038/nsmb1103. PMC 1584284. PMID 16732284.
  10. ^ Gurevich VV, Gurevich EV (June 2006). "The structural basis of arrestin-mediated regulation of G-protein-coupled receptors". Pharmacol. Ther. 110 (3): 465–502. doi:10.1016/j.pharmthera.2005.09.008. PMC 2562282. PMID 16460808.
  11. ^ Collins BM (November 2008). "The structure and function of the retromer protein complex". Traffic. 9 (11): 1811–22. doi:10.1111/j.1600-0854.2008.00777.x. PMID 18541005. S2CID 28028098.
  12. ^ Kerr MC, Bennetts JS, Simpson F, Thomas EC, Flegg C, Gleeson PA, Wicking C, Teasdale RD (November 2005). "A novel mammalian retromer component, Vps26B". Traffic. 6 (11): 991–1001. doi:10.1111/j.1600-0854.2005.00328.x. PMID 16190980. S2CID 31954489.
  13. ^ Bugarcic A, Zhe Y, Kerr MC, Griffin J, Collins BM, Teasdale RD (December 2011). "Vps26A and Vps26B subunits define distinct retromer complexes". Traffic. 12 (12): 1759–73. doi:10.1111/j.1600-0854.2011.01284.x. PMID 21920005. S2CID 24548200.

Further reading

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