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Protein VPS26A PDB 2fau.png
Available structures
PDB Ortholog search: PDBe RCSB
Aliases VPS26A, HB58, Hbeta58, PEP8A, VPS26, VPS26 retromer complex component A, VPS26, retromer complex component A
External IDs MGI: 1353654 HomoloGene: 68420 GeneCards: VPS26A
RNA expression pattern
PBB GE VPS26A 201807 at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 10: 69.12 – 69.17 Mb Chr 10: 62.45 – 62.49 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse

Vacuolar protein sorting-associated protein 26A is a protein that in humans is encoded by the VPS26A gene.[3][4][5]

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.[5]


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.[6][7] 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.[8] 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.[9]

Vps26B paralogue[edit]

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.[10]

X-ray crystallography revealed that the structures of both Vps26A and Vps26B share a similar bilobal β-sandwich structure and possess 70% sequence homology.[6] 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. Interestingly, 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.[11]


  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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. PMID 1638986. 
  4. ^ 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. doi:10.1073/pnas.95.14.8175. PMC 20949Freely accessible. PMID 9653160. 
  5. ^ a b "Entrez Gene: VPS26A vacuolar protein sorting 26 homolog A (S. pombe)". 
  6. ^ 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. 
  7. ^ 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 1584284Freely accessible. PMID 16732284. 
  8. ^ 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 2562282Freely accessible. PMID 16460808. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 

Further reading[edit]