{PDOC51205} {PS51205; VPS9} {BEGIN} *********************** * VPS9 domain profile * *********************** Rab proteins form a family of signal-transducing GTPases that cycle between active GTP-bound and inactive GDP-bound forms. The Rab5 GTPase is an essential regulator of endocytosis and endosome biogenesis. Rab5 is activated by GDP-GTP exchange factors (GEFs) that contain a VPS9 domain and generate the Rab5-GTP complex [1]. The VPS9 domain catalyzes nucleotide exchange on Rab5 or the yeast homolog VPS21. The domain has a length of ~140 residues and forms the central part of the yeast VPS9 (vacuolar protein sorting-associated) protein, which acts as a GEF for VPS21. Some domains which can occur in combination with the VPS9 domain are CUE (see ), A20-type zinc finger (see ), Ras-associating (RA) (see ), SH2 (see ), RCC1 (see ), DH (see ), PH (see ), rasGAP (see ), MORN and ankyrin repeat (see ). Structurally, the VPS9 domain adopts a layered fold of six alpha helices (see ). Conserved residues from the fourth and sixth helices and the loops N-terminal to these helices form the surface that interacts with Rab5 and Rab21 [2]. Some proteins known to contain a VPS9 domain: - Fungal Vacuolar Protein Sorting-associated protein VPS9, a guanine nucleotide exchange factor for the Rab-like GTPase VPS21. VPS9 is needed for the transport of proteins from biosynthetic and endocytic pathways into the vacuole. - Mammalian Rab5 GDP/GTP exchange factor or Rabex-5 (Rababtin-5 associated exchange factor for Rab5), catalyzes nucleotide exchange on RAB5A. Rabex-5 promotes endocytic membrane fusion and is involved in membrane trafficking of recycling endosomes. - Mammalian Ras and Rab interactor 1 (RIN1), 2 (RIN2) and 3 (RIN3). - Mammalian alsin or Amyotrophic Lateral Sclerosis protein 2 (ALS2). Different juvenile-onset forms of neurodegenerative diseases (ALS2, JPLS, IAHSP) are caused by mutations in the ALS2 gene, which result in truncated alsin lacking the C-terminal part of the VPS9 domain. - Fruit fly protein sprint, which is a RIN homologue. - Caenorhabditis elegans RME-6 protein, which is conserved among metazoans. The profile we developed covers the entire VPS9 domain. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: May 2006 / First entry. [ 1] Carney D.S., Davies B.A., Horazdovsky B.F. "Vps9 domain-containing proteins: activators of Rab5 GTPases from yeast to neurons." Trends Cell Biol. 16:27-35(2006). PubMed=16330212; DOI=10.1016/j.tcb.2005.11.001 [ 2] Delprato A., Merithew E., Lambright D.G. "Structure, exchange determinants, and family-wide rab specificity of the tandem helical bundle and Vps9 domains of Rabex-5." Cell 118:607-617(2004). PubMed=15339665; DOI=10.1016/j.cell.2004.08.009 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}