View source for 8dgq


==Crystal structure of p120RasGAP SH2-SH3-SH2 in complex with p190RhoGAP doubly phosphorylated peptide==
<StructureSection load='8dgq' size='340' side='right'caption='[[8dgq]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8dgq]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DGQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DGQ FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8dgq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dgq OCA], [https://pdbe.org/8dgq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dgq RCSB], [https://www.ebi.ac.uk/pdbsum/8dgq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dgq ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/RASA1_HUMAN 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:[https://omim.org/entry/608354 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.<ref>PMID:14639529</ref>   Defects in RASA1 are a cause of Parkes Weber syndrome (PKWS) [MIM:[https://omim.org/entry/608355 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 ==
[https://www.uniprot.org/uniprot/RASA1_HUMAN 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.<ref>PMID:8360177</ref> <ref>PMID:11389730</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:36417908</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8dgq" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ras GTPase activating protein|Ras GTPase activating protein]]
*[[Rho GTPase activating protein 3D structures|Rho GTPase activating protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Boggon TJ]]
[[Category: Stiegler AL]]
[[Category: Vish KJ]]