The GTPase-activating protein p120RasGAP has an evolutionarily conserved “FLVR-unique” SH2 domain
Year: 2020
Type: article
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 ( 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 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."
Source: Journal of Biological Chemistry
Institutions: Yale University, Yale Cancer Center
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
Awards: G102163711, G107546177, G1313983767, G1664757510, G1728560155, Modulating RHO cascades for new cardiovascular therapeutics, G2287611682, G262962599, G2784524989, G3075337988, G498139845, G5384392517, G5607048534, G6848031779, G6918803902, Upgrade of a home source macromolecular X-ray diffraction system., G9000038451, G9000104359, G969889393, G993149817
OpenAlex ID: W3035354493