PROSITE documentation PDOC50238

Rho GTPase-activating proteins domain profile

Small G proteins of the Rho family, which includes Rho, Rac and Cdc42, regulate phosphorylation pathways that control a range of biological functions including cytoskeleton formation and cell proliferation. Rho proteins act as molecular switches, with an active GTP-bound form and an inactive GDP-bound form. The inactive GDP bound form is promoted by GTPase-activating proteins (GAPs). GAP proteins specific for Rho contain a conserved region of around 200 amino-acid residues, the Rho-GAP domain. This domain can accelerate the GTP hydrolysis activity of Rho by five orders of magnitude [1]. RhoGAP domains are usually associated with other signaling modules like SH2 (see <PDOC50001>), SH3 (see <PDOC50002>) or PH (see <PDOC50003>).

Like other GAP domains Rho-GAP is exclusively helical (nine helices) (see <PDB:1RGP>) [2]. The core of the domain forms a four-helix bundle. The most conserved residues across the family are located on the bundle face that interacts with the G protein [3]. Rho-GAP domain like Ras-GAP supplies an arginine residue in trans into the active site of the G protein which confers a self-stimulatory GAP activity through homophilic interaction [4].

Some of the proteins containing a RhoGAP domain are listed below:

• Mammalian ARAP 1,2 and 3 proteins, a family of GTPase activating proteins that contains both a RhoGAP and a ARFGAP domains (see <PDOC50115>). They can regulate Rho or ARF G proteins according to their localization in the cell.
• Vertebrate β-chimaerin protein, a GTPase activating protein for the Rho- like GTPase Rac.
• Mammalian Nadrin protein, a neuron-specific GTPase-activating protein involved in regulated exocytosis.
• Mammalian unconventional myosin-9b.
• Mammalian breakpoint cluster region protein (BCR) and Drosophila Rotund protein, GTPase-activating proteins for Rac and Cdc42.
• Mammalian Rho-GAP hematopoietic protein C1.
• Mammalian Rho-GTPase-activating protein 6. It promotes continuous elongation of cytoplasmic processes during cell motility and simultaneous retraction of the cell body changing the cell morphology.
• Mammalian phosphatidylinositol 3-kinase regulatory α subunit, an adapter subunit of the phosphatidylinositol 3-kinase (PI3K). It has a critical role in signal transduction pathways originating from a variety of membrane-bound receptors.
• Mammalian Inositol polyphosphate 5-phosphatase OCRL-1 (EC 3.1.3.-). It may function in lysosomal membrane trafficking by regulating the specific pool of phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes.
• Mammalian type II inositol-1,4,5-trisphosphate 5-phosphatase involved in signal-terminating reaction (EC 3.1.3.56.).
• Yeast LRG1 and SAC7 proteins, the two major Rho GTPase-activating proteins. The SAC7 protein is involved in assembly of actin.
• Yeast BEM2 protein, a GTPase activating protein involved in the control of cellular morphogenesis.

The profile we developed covers the whole domain.