GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1)
The protein contains 1478 amino acids for an estimated molecular weight of 164980 Da.
Acts both as a GTPase-activating protein (GAP) and a guanine nucleotide exchange factor (GEF), and participates in various processes such as endocytosis, insulin receptor internalization or LC2A4/GLUT4 trafficking. Acts as a GEF for the Ras-related protein RAB31 by exchanging bound GDP for free GTP, leading to regulate LC2A4/GLUT4 trafficking. In the absence of insulin, it maintains RAB31 in an active state and promotes a futile cycle between LC2A4/GLUT4 storage vesicles and early endosomes, retaining LC2A4/GLUT4 inside the cells. Upon insulin stimulation, it is translocated to the plasma membrane, releasing LC2A4/GLUT4 from intracellular storage vesicles. Also involved in EGFR trafficking and degradation, possibly by promoting EGFR ubiquitination and subsequent degradation by the proteasome. Has GEF activity for Rab5 and GAP activity for Ras. (updated: April 1, 2015)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- 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.
- 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.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- 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.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
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.
This protein is annotated as membranous in Gene Ontology.
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The reference OMIM entry for this protein is 611714
Gtpase-activating protein and vps9 domains 1; gapvd1
Rab5-activating protein 6; rap6
Rab5 exchange factor; gapex5
Kiaa1521
CLONING
Hunker et al. (2006) identified a Rab GTPase guanine nucleotide exchange factor (GEF), which they named RAP6 (Rab5-activating protein-6), as a protein of approximately 150 kD that interacted with Rab5a (179512) in HeLa cells. After isolating and characterizing the protein by mass spectrometry, they identified it by database analysis as GAPVD1. The deduced 1,439-amino acid protein has a predicted molecular mass of 158 kD. It contains a C-terminal Vps9-like motif, which is found in other Rab5 GEFs, and an N-terminal RasGAP-like domain (RGD) similar to those found in GAP proteins that specifically interact with Ras proteins. An antibody raised to RAP6 localized the protein to the plasma membrane and intracellular vesicles.GENE FUNCTION
Hunker et al. (2006) confirmed that RAP6 binds to Rab5 and Ras through the Vps9 and RGD domains, respectively. Overexpression of RAP6 affected both fluid phase and receptor-mediated endocytosis. Hunker et al. (2006) suggested that RAP6 may play a role in endocytosis by regulating endosome morphology. Su et al. (2007) studied the same protein, which they called Rab5 exchange factor (GAPEX5), in epidermal growth factor receptor (EGFR; 131550) trafficking and degradation. Depletion of the protein delayed EGFR degradation, whereas overexpression had the reverse effect. Su et al. (2007) proposed that GAPEX5 affects EGFR degradation by mediating receptor ubiquitination through its RGD domain and may be an important mediator of carcinogenesis resulting from mutations in the Ras proteins. Kitano et al. (2008) found that GAPEX5 is the guanine nucleotide exchange factor essential for activation of RAB5 (179512) during engulfment of apoptotic cells. GAPEX5 was bound to a microtubule tip-associating protein, EB1 (603108), whose depletion inhibited Rab5 activation during phagocytosis. Kitano et al. (2008) therefore proposed a mechanistic model in which the recruitment of GAPEX5 to phagosomes through the microtubule network induces transient RAB5 activation.MAPPING
By database analysis, Hunker et al. (2006) identified the GAPVD1 gene on chromosome 9q33.3. ... More on the omim web site
Feb. 23, 2019: Protein entry updated
Automatic update: model status changed
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 611714 was added.