VPS9 domain (IPR003123)
Short name: VPS9
Overlapping homologous superfamilies
- VPS9 domain superfamily (IPR037191)
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 [PMID: 16330212]. The VPS9 domain catalyzes nucleotide exchange on Rab5 or the yeast homologue 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, 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 the loops N-terminal to these helices form the surface that interacts with Rab5 and Rab21 [PMID: 15339665].
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.