Biology:VPS26A

Short description: Protein-coding gene in the species Homo sapiens

Generic protein structure example

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.

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.

Structure

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. 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. 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.

Vps26B paralogue

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.

X-ray crystallography revealed that the structures of both Vps26A and Vps26B share a similar bilobal β-sandwich structure and possess 70% sequence homology. 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.

Further reading

• "Cloning and Functional Analysis of cDNAs with Open Reading Frames for 300 Previously Undefined Genes Expressed in CD34+ Hematopoietic Stem/Progenitor Cells". Genome Res. 10 (10): 1546–60. 2001. doi:10.1101/gr.140200. PMID 11042152. 
• "Human Orthologs of Yeast Vacuolar Protein Sorting Proteins Vps26, 29, and 35: Assembly into Multimeric Complexes". Mol. Biol. Cell 11 (12): 4105–16. 2001. doi:10.1091/mbc.11.12.4105. PMID 11102511. 
• "Vps26p, a Component of Retromer, Directs the Interactions of Vps35p in Endosome-to-Golgi Retrieval". Mol. Biol. Cell 12 (10): 3242–56. 2002. doi:10.1091/mbc.12.10.3242. PMID 11598206. 
• "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. 2003. doi:10.1073/pnas.242603899. PMID 12477932. Bibcode: 2002PNAS...9916899M. 
• "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. 2004. doi:10.1038/ng1285. PMID 14702039. 
• "The DNA sequence and comparative analysis of human chromosome 10". Nature 429 (6990): 375–81. 2004. doi:10.1038/nature02462. PMID 15164054. Bibcode: 2004Natur.429..375D. 
• "The mammalian retromer regulates transcytosis of the polymeric immunoglobulin receptor". Nat. Cell Biol. 6 (8): 763–9. 2004. doi:10.1038/ncb1153. PMID 15247922. 
• "Exportin 7 defines a novel general nuclear export pathway". EMBO J. 23 (16): 3227–36. 2005. doi:10.1038/sj.emboj.7600338. PMID 15282546. 
• "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. 2004. doi:10.1101/gr.2596504. PMID 15489334. 
• "A novel mammalian retromer component, Vps26B". Traffic 6 (11): 991–1001. 2006. doi:10.1111/j.1600-0854.2005.00328.x. PMID 16190980. 
• "Model-guided microarray implicates the retromer complex in Alzheimer's disease". Ann. Neurol. 58 (6): 909–19. 2006. doi:10.1002/ana.20667. PMID 16315276. 
• "An Essential Role for SNX1 in Lysosomal Sorting of Protease-activated Receptor-1: Evidence for Retromer-, Hrs-, and Tsg101-independent Functions of Sorting Nexins". Mol. Biol. Cell 17 (3): 1228–38. 2006. doi:10.1091/mbc.E05-09-0899. PMID 16407403. 
• "The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain". Nat. Struct. Mol. Biol. 13 (6): 540–8. 2006. doi:10.1038/nsmb1103. PMID 16732284. 
• "No association of vacuolar protein sorting 26 polymorphisms with Alzheimer's disease". Neurobiol. Aging 28 (6): 883–4. 2007. doi:10.1016/j.neurobiolaging.2006.05.009. PMID 16784798. 
• "Interchangeable but Essential Functions of SNX1 and SNX2 in the Association of Retromer with Endosomes and the Trafficking of Mannose 6-Phosphate Receptors". Mol. Cell. Biol. 27 (3): 1112–24. 2007. doi:10.1128/MCB.00156-06. PMID 17101778.