6way | pdb_00006way
C-terminal SH2 domain of p120RasGAP in complex with p190RhoGAP phosphotyrosine peptide
Structural highlights
DiseaseRASA1_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. FunctionRASA1_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] Publication Abstract from PubMedThe Src homology 2 (SH2) domain has a highly conserved architecture that recognizes linear phosphotyrosine motifs and is present in a wide range of signaling pathways across different evolutionary taxa. A hallmark of SH2 domains is the arginine residue in the conserved "FLVR" motif that forms a direct salt bridge with bound phosphotyrosine. Here, we solve the X-ray crystal structures of the C-terminal SH2 domain of p120RasGAP (RASA1) in its apo and peptide-bound form. We find that the arginine residue in the FLVR motif does not directly contact pTyr-1087 of a bound phosphopeptide derived from p190RhoGAP; rather, it makes an intramolecular salt bridge to an aspartic acid. Unexpectedly, coordination of phosphotyrosine is achieved by a modified binding pocket which appears early in evolution. Using isothermal titration calorimetry, we find that substitution of the FLVR arginine R377A does not cause a significant loss of phosphopeptide binding, but rather a tandem substitution of R398A (SH2 position betaD4) and K400A (SH2 position betaD6) is required to disrupt the binding. These results indicate a hitherto unrecognized diversity in SH2 domain interactions with phosphotyrosine, and classify the C-terminal SH2 domain of p120RasGAP as "FLVR-unique." The GTPase-activating protein p120RasGAP has an evolutionarily conserved "FLVR-unique" SH2 domain.,Jaber Chehayeb R, Wang J, Stiegler AL, Boggon TJ J Biol Chem. 2020 Jun 15. pii: RA120.013976. doi: 10.1074/jbc.RA120.013976. PMID:32540970[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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