8dgq

Crystal structure of p120RasGAP SH2-SH3-SH2 in complex with p190RhoGAP doubly phosphorylated peptide

spinqualitylabelsall models 8dgq, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dgq is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.95Å Ligands: MLI, PTR Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. 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. Publication Abstract from PubMed p120RasGAP is a multidomain GTPase-activating protein for Ras. The presence of two Src homology 2 domains in an SH2-SH3-SH2 module raises the possibility that p120RasGAP simultaneously binds dual phosphotyrosine residues in target proteins. One known binding partner with two proximal phosphotyrosines is p190RhoGAP, a GTPase-activating protein for Rho GTPases. Here, we present the crystal structure of the p120RasGAP SH2-SH3-SH2 module bound to a doubly tyrosine-phosphorylated p190RhoGAP peptide, revealing simultaneous phosphotyrosine recognition by the SH2 domains. The compact arrangement places the SH2 domains in close proximity resembling an SH2 domain tandem and exposed SH3 domain. Affinity measurements support synergistic binding, while solution scattering reveals that dual phosphotyrosine binding induces compaction of this region. Our studies reflect a binding mode that limits conformational flexibility within the SH2-SH3-SH2 cassette and relies on the spacing and sequence surrounding the two phosphotyrosines, potentially representing a selectivity mechanism for downstream signaling events. Tandem engagement of phosphotyrosines by the dual SH2 domains of p120RasGAP.,Stiegler AL, Vish KJ, Boggon TJ Structure. 2022 Dec 1;30(12):1603-1614.e5. doi: 10.1016/j.str.2022.10.009. Epub , 2022 Nov 22. PMID:36417908 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ras GTPase activating protein Rho GTPase activating protein 3D structures

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