The NMR structure of the P395S mutant of the N-SH2 domain of the p85 subunit of PI3-kinase: An SH2 domain with altered specificity

Ulrich Gunther, B Weyrauch, X Zhang, B Schaffhausen

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Understanding the specificity of Src homology 2 (SH2) domains is important because of their critical role in cell signaling. Previous genetic analysis has characterized mutants of the N-terminal src homology 2 (SH2) domain of the p85 subunit of phosphoinositide 3-kinase (PI3K). The P395S mutant exhibits a specificity for phosphopeptide binding different from that of the wild-type SH2. The P395S mutant has an increased affinity for the platelet-derived growth factor receptor (PDGFr) compared to polyomavirus middle T antigen (MT). Solution structures of the P395S mutant of the p85 N-SH2 alone and complexed to a PDGFr phosphopeptide were determined to explain the change in specificity. Chemical shift perturbations caused by different peptides were compared for mutant and wild-type structures. The results show that the single P395S mutation has broad effects on the structure. Furthermore, they provide a rationale for the observed changes in binding preference.
Original languageEnglish
Pages (from-to)11120-11127
Number of pages8
JournalBiochemistry
Volume42
DOIs
Publication statusPublished - 30 Sep 2003

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