6WAX

C-terminal SH2 domain of p120RasGAP

Summary for 6WAX

• Entry DOI: 10.2210/pdb6wax/pdb
• Descriptor: Ras GTPase-activating protein 1, SULFATE ION, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: sh2 domain, rasgap, phosphopeptide, phosphotyrosine, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 25500.41

Authors

Jaber Chehayeb, R.,Wang, J.,Stiegler, A.L.,Boggon, T.J. (deposition date: 2020-03-26, release date: 2020-06-17, Last modification date: 2023-10-18)

Primary citation

Jaber Chehayeb, R.,Wang, J.,Stiegler, A.L.,Boggon, T.J.
The GTPase-activating protein p120RasGAP has an evolutionarily conserved "FLVR-unique" SH2 domain.
J.Biol.Chem., 295:10511-10521, 2020

PubMed Abstract: The 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 () in its apo and peptide-bound form. We find that the arginine residue in the FLVR motif does not directly contact pTyr 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 that 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 βD4) and K400A (SH2 position βD6) 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."

PubMed: 32540970
DOI: 10.1074/jbc.RA120.013976

Experimental method

X-RAY DIFFRACTION (1.5 Å)