Vacuolar protein sorting-associated protein 35 (VPS35)

The protein contains 796 amino acids for an estimated molecular weight of 91707 Da.

 

Acts as component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway (PubMed:30213940). The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5 (Probable). Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA) (PubMed:15078903, PubMed:15247922, PubMed:20164305). Required for endosomal localization of WASHC2C (PubMed (updated: April 7, 2021)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  3. Wilson and co-workers. (2016) Comparison of the Proteome of Adult and Cord Erythroid Cells, and Changes in the Proteome Following Reticulocyte Maturation. Mol Cell Proteomics. 15(6), 1938-1946.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  6. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete
TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.

Interpro domains
Total structural coverage: 37%
Model score: 51

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VariantDescription
dbSNP:rs193077277
dbSNP:rs183554824
dbSNP:rs188245364
Found in a patient with Parkinson disease
Found in a patient with Parkinson disease
Found in a patient with Parkinson disease
dbSNP:rs34687100
PARK17
dbSNP:rs749516404
dbSNP:rs192419029
Found in a consanguineous family with intellectual disability; unknown pathological significance

Biological Process

Endocytic recycling GO Logo
Intracellular protein transport GO Logo
Lysosome organization GO Logo
Mitochondrial fragmentation involved in apoptotic process GO Logo
Mitochondrion to lysosome transport GO Logo
Negative regulation of cell death GO Logo
Negative regulation of cellular protein localization GO Logo
Negative regulation of gene expression GO Logo
Negative regulation of inflammatory response GO Logo
Negative regulation of late endosome to lysosome transport GO Logo
Negative regulation of lysosomal protein catabolic process GO Logo
Negative regulation of neuron death GO Logo
Negative regulation of protein homooligomerization GO Logo
Neurotransmitter receptor transport, endosome to plasma membrane GO Logo
Neurotransmitter receptor transport, endosome to postsynaptic membrane GO Logo
Positive regulation of canonical Wnt signaling pathway GO Logo
Positive regulation of cellular protein catabolic process GO Logo
Positive regulation of dopamine biosynthetic process GO Logo
Positive regulation of dopamine receptor signaling pathway GO Logo
Positive regulation of gene expression GO Logo
Positive regulation of locomotion involved in locomotory behavior GO Logo
Positive regulation of mitochondrial fission GO Logo
Positive regulation of Wnt protein secretion GO Logo
Protein destabilization GO Logo
Protein localization to endosome GO Logo
Protein localization to organelle GO Logo
Regulation of cellular protein metabolic process GO Logo
Regulation of dendritic spine maintenance GO Logo
Regulation of macroautophagy GO Logo
Regulation of mitochondrion organization GO Logo
Regulation of presynapse assembly GO Logo
Regulation of protein stability GO Logo
Regulation of terminal button organization GO Logo
Retrograde transport, endosome to Golgi GO Logo
Retrograde transport, endosome to plasma membrane GO Logo
Synapse assembly GO Logo
Transcytosis GO Logo
Vesicle-mediated transport in synapse GO Logo
Viral process GO Logo
Voluntary musculoskeletal movement GO Logo
Wnt signaling pathway GO Logo

The reference OMIM entry for this protein is 601501

Vacuolar protein sorting 35, yeast, homolog of; vps35
Mem3, mouse, homolog of; mem3

DESCRIPTION

The VPS35 gene encodes a component of the retromer cargo-recognition complex critical for endosome-trans-Golgi trafficking and the recycling of membrane-associated proteins (summary by Vilarino-Guell et al., 2011).

CLONING

To study the molecular function of genes expressed during preimplantation development, Hwang et al. (1996) isolated a novel maternal transcript, stage specific embryonic cDNA-26 (SSEC-26), from a partial subtraction library of mouse unfertilized eggs and preimplantation embryos. The SSEC-26 transcript was abundant in the unfertilized egg and also actively transcribed from the newly formed zygotic genome. On the basis of its expression in eggs and embryos, this mouse gene was named Mem3 (maternal-embryonic-3). The deduced amino acid sequence of Mem3 resembles that of the yeast VPS35 protein in 2 separate domains. Hwang et al. (1996) assembled a cDNA sequence of the putative human homolog of Mem3 (VPS35) with partial clones from an EST database. By EST database searching for sequences homologous to yeast VPS35, Zhang et al. (2000) identified human VPS35. They cloned a full-length cDNA from a human testis cDNA library. The deduced 796-amino acid protein contains 2 polyadenylation signals. Both human and yeast VPS35, which share 30% identity, lack a hydrophobic region. Northern blot analysis revealed bands at 5.5, 3.6, and 3.0 kb. The major 3.6-kb transcript was expressed at highest levels in brain, heart, testis, ovary, small intestine, spleen, skeletal muscle, and placenta, at moderate levels in pancreas, thymus, prostate, and colon, and at low levels in lung, liver, kidney, and peripheral blood leukocytes. Weaker expression of the 3.0-kb transcript followed the same distribution except in brain, where it was not detected. The 5.5-kb transcript showed low expression in all tissues tested. Zhang et al. (2000) also cloned mouse Vps35, which encodes a 796-amino acid protein containing a single polyadenylation signal. This sequence shares 99% identity with human VPS35 and 49% similarity with yeast VPS35. Northern blot analysis detected a single 3.4-kb transcript expressed at varying levels in all tissues examined. Edgar and Polak (2000) independently cloned VPS35 from a human lung cDNA library. Their sequence analysis revealed the presence of a third polyadenylation signal. They found ubiquitous expression of transcripts of 2.8, 3.3, and 6.8 kb corresponding to the use of all 3 polyadenylation signals. Expression was highest in heart, skeletal muscle, kidney, and brain, and lowest in peripheral blood leukocytes. In brain, only the 3.3-kb transcript was observed. By sequence analysis, Edgar and Polak (2000) determined that the protein is predominantly alpha-helical.

BIOCHEMICAL FEATURES

- Crystal Structure Hierro et al. (2007) reported the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 acts as a scaffold for the C-terminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. Electron microscopy showed that the intact VPS26-VPS29-VPS35 complex is a stick-shaped, flexible structure, approximately 21 nanometers long. A hybrid structural model derived from crystal structures, electron microscopy, interaction studies, and bioinformatics showed th ... More on the omim web site

Subscribe to this protein entry history

April 10, 2021: Protein entry updated
Automatic update: Entry updated from uniprot information.

May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 601501 was added.

Feb. 24, 2016: Protein entry updated
Automatic update: model status changed