Rab proteins form a family of signal-transducing GTPases that cycle betweenactive GTP-bound and inactive GDP-bound forms. The Rab5 GTPase is an essentialregulator of endocytosis and endosome biogenesis. Rab5 is activated by GDP-GTPexchange factors (GEFs) that contain a VPS9 domain and generate the Rab5-GTPcomplex []. The VPS9 domain catalyzes nucleotide exchange on Rab5 or theyeast homologue VPS21. The domain has a length of ~140 residues and forms thecentral part of the yeast VPS9 (vacuolar protein sorting-associated) protein,which acts as a GEF for VPS21. Some domains which canoccur in combinationwith the VPS9 domain are CUE, A20-type zinc finger, Ras-associating (RA), SH2,RCC1, DH, PH, rasGAP, MORN and ankyrin repeat.Structurally, the VPS9 domain adopts a layered fold of six alpha helices. Conserved residues from the fourth and sixth helices and theloops N-terminal to these helices form the surface that interacts with Rab5and Rab21 [].Some proteins known to contain a VPS9 domain:Fungal Vacuolar Protein Sorting-associated protein VPS9, a guaninenucleotide exchange factor for the Rab-like GTPase VPS21. VPS9 is neededfor the transport of proteins from biosynthetic and endocytic pathways intothe vacuole.Mammalian Rab5 GDP/GTP exchange factor or Rabex-5 (Rababtin-5 associatedexchange factor for Rab5), catalyzes nucleotide exchange on RAB5A. Rabex-5promotes endocytic membrane fusion and is involved in membrane traffickingof 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 truncatedalsin 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.
