Ras-related protein Rab-5A (RAB5A)

The protein contains 215 amino acids for an estimated molecular weight of 23659 Da.

 

Small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Active GTP-bound form is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB5A is required for the fusion of plasma membranes and early endosomes (PubMed:10818110, PubMed:14617813, PubMed:16410077, PubMed:15378032). Contributes to the regulation of filopodia extension (PubMed:14978216). Required for the exosomal release of SDCBP, CD63, PDCD6IP and syndecan (PubMed:22660413). Regulates maturation of apoptotic cell-containing phagosomes, probably downstream of DYN2 and PIK3C3 (By similarity). (updated: Oct. 16, 2019)

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. 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.
  3. 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.
  4. 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.
  5. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  6. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  7. 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.

This protein is annotated as membranous in Gene Ontology, is annotated as membranous in UniProt.


Interpro domains
Total structural coverage: 100%
Model score: 0
No model available.

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The reference OMIM entry for this protein is 179512

Ras-associated protein rab5a; rab5a
Rab5

CLONING

The S. cerevisiae YPT1 and SEC4 genes encode Ras-related GTP-binding proteins involved in the regulation of secretion. Mammalian cells express a large number of RAB proteins, GTP-binding proteins closely related to YPT1 and SEC4. By screening a human pheochromocytoma library with probes derived from the SEC4 gene and from various rat and human RAB cDNAs, Zahraoui et al. (1989) isolated cDNAs encoding RAB1 (179508), RAB2 (179509), RAB3A (179490), RAB3B (179510), RAB4 (179511), RAB5, and RAB6 (179513). Except for the closely related RAB3A and RAB3B, the deduced human RAB proteins share 32 to 50% homology. The predicted 214-amino acid RAB5 protein is 31% and 38% identical to SEC4 and YPT1, respectively. All 6 human RAB proteins tested bound GTP and exhibited GTPase activities in vitro. Northern blot analysis revealed that RAB5 was expressed as 2.7- and 2.8-kb mRNAs in a human fibroblast cell line.

GENE FUNCTION

Bucci et al. (1992) demonstrated that RAB5 is a rate-limiting component of the machinery regulating the kinetics of membrane traffic in the early endocytic pathway. Stenmark et al. (1995) reported that rabaptin-5 (603616) is an effector of RAB5 that transmits the signal of the active GTP-bound RAB5 conformation to the membrane docking and/or fusion apparatus. Xiao et al. (1997) found that tuberin (191092) exhibits substantial GTPase-activating protein (GAP) activity towards RAB5, and that rabaptin-5 mediates the tuberin association with RAB5. The authors suggested that tuberin functions as a RAB5GAP in vivo to negatively regulate RAB5-GTP activity in endocytosis. Epidermal growth factor receptor (EGFR; 131550) signaling involves small GTPases of the Rho family, and EGFR trafficking involves small GTPases of the Rab family. Lanzetti et al. (2000) reported that the EPS8 (600206) protein connects these signaling pathways. EPS8 is a substrate of EGFR that is held in a complex with SOS1 (182530) by the adaptor protein E3B1 (603050), thereby mediating activation of RAC (602048). Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et al. (2000) showed that RNTRE is a RAB5 GTPase-activating protein whose activity is regulated by EGFR. By entering in a complex with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR. Furthermore, RNTRE diverts EPS8 from its RAC-activating function, resulting in the attenuation of RAC signaling. Thus, depending on its state of association with E3B1 or RNTRE, EPS8 participates in both EGFR signaling through RAC and EGFR trafficking through RAB5. Otomo et al. (2003) showed that the ALS2 protein (ALSIN; 606352) specifically binds to small GTPase RAB5 and functions as a guanine nucleotide exchange factor (GEF) for RAB5. Ectopically expressed ALS2 localized with RAB5 and early endosome antigen-1 (EEA1; 605070) onto early endosomal compartments and stimulated the enlargement of endosomes in cultured cortical neurons. The C terminus of ALS2 carrying a VPS9 domain mediated not only the activation of RAB5 via a guanine-nucleotide exchanging reaction but also the endosomal localization of ALS2, whereas the N-terminal half containing the RCC1 (179710)-like domain acted suppressive in its membranous localization. The DH/PH domain in the middle portion of ALS2 enhanced the VPS9 domain-mediated endosome fusions. Otomo et al. (2003) hypothesized that a perturbation of endosomal dynamics caused by loss of the ALS2 functional domain that confers RAB5 GEF activity mi ... More on the omim web site

Subscribe to this protein entry history

Oct. 27, 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 179512 was added.