Rab21 is a Rab GTPase that has been shown to colocalize with and affect the morphology of early endosomes []. In Dictyostelium, GTP-bound Rab21, together with two novel LIM domain proteins, LimF and ChLim, has been shown to regulate phagocytosis [].Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [, ].
This domain is found in the catalytic core RABEX-5 present in Homo sapiens. RABEX, also known as Rab GTPase exchange factors, regulate endocytic trafficking through activation of the Rab families RAB5, RAB21 and RAB22. The domain is helical in nature [].
This domain is found in eukaryotes, and is approximately 220 amino acids in length. It is found in association with , . It is found is the middle region of SBF1 and SBF2, members of the myotubularin family. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Mutations of SBF2 are implicated in Charcot-Marie-Tooth disease []. SBF2 is a guanine nucleotide exchange factor (GEF) which activates RAB21 and possibly RAB28 [, ].
Lpg0393 is a Legionella pneumophila effector protein. Structure analysis reveals that it has two domains, the N-terminal domain is a Vps9-like domain, which is structurally most similar to the catalytic core of human Rabex-5 that activates the endosomal Rab proteins Rab5, Rab21 and Rab22. The C-terminal domain is a helical bundle domain. The C-terminal helical bundle of Lpg0393 corresponds to the N-terminal helical bundle of Rabex-5, it lacks an obvious region that corresponds to the membrane-binding motif of Rabex-5. One possibility may be that Lpg0393 localization to endosomes depends on an unknown Legionella effector [].
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 []. The VPS9 domain catalyses 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 theloops N-terminal to these helices form the surface that interacts with Rab5and Rab21 [].
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.
