1wer | pdb_00001wer
RAS-GTPASE-ACTIVATING DOMAIN OF HUMAN P120GAP
Structural highlights
Disease[RASA1_HUMAN] Note=Mutations in the SH2 domain of RASA seem to be oncogenic and cause basal cell carcinomas. Defects in RASA1 are the cause of capillary malformation-arteriovenous malformation (CMAVM) [MIM:608354]. CMAVM is a disorder characterized by atypical capillary malformations that are multiple, small, round to oval in shape and pinkish red in color. These capillary malformations are associated with either arteriovenous malformation, arteriovenous fistula, or Parkes Weber syndrome.[1] Defects in RASA1 are a cause of Parkes Weber syndrome (PKWS) [MIM:608355]. PKWS is a disorder characterized by a cutaneous flush with underlying multiple micro-arteriovenous fistulas, in association with soft tissue and skeletal hypertrophy of the affected limb. Function[RASA1_HUMAN] Inhibitory regulator of the Ras-cyclic AMP pathway. Stimulates the GTPase of normal but not oncogenic Ras p21; this stimulation may be further increased in the presence of NCK1.[2] [3] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRas-related GTP-binding proteins function as molecular switches which cycle between GTP-bound 'on'- and GDP-bound 'off'-states. GTP hydrolysis is the common timing mechanism that mediates the return from the 'on' to the 'off'-state. It is usually slow but can be accelerated by orders of magnitude upon interaction with GTPase-activating proteins (GAPs). In the case of Ras, a major regulator of cellular growth, point mutations are found in approximately 30% of human tumours which render the protein unable to hydrolyse GTP, even in the presence of Ras-GAPs. The first structure determination of a GTPase-activating protein reveals the catalytically active fragment of the Ras-specific p120GAP (ref. 2), GAP-334, as an elongated, exclusively helical protein which appears to represent a novel protein fold. The molecule consists of two domains, one of which contains all the residues conserved among different GAPs for Ras. From the location of conserved residues around a shallow groove in the central domain we can identify the site of interaction with Ras x GTP. This leads to a model for the interaction between Ras and GAP that satisfies numerous biochemical and genetic data on this important regulatory process. Crystal structure of the GTPase-activating domain of human p120GAP and implications for the interaction with Ras.,Scheffzek K, Lautwein A, Kabsch W, Ahmadian MR, Wittinghofer A Nature. 1996 Dec 12;384(6609):591-6. PMID:8955277[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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