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 <PDOC51140>), A20-type zinc finger (see <PDOC51036>), Ras-associating (RA) (see <PDOC50200>), SH2 (see <PDOC50001>), RCC1 (see <PDOC00544>), DH (see <PDOC00605>), PH (see <PDOC50003>), rasGAP (see <PDOC00438>), MORN and ankyrin repeat (see <PDOC50088>).

Structurally, the VPS9 domain adopts a layered fold of six α helices (see <PDB:1TXU>). 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.