Nuclear magnetic resonance structure of the P395S mutant of the N-SH2 domain of the p85 subunit of PI3 kinase: an SH2 domain with altered specificity.
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.
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010748:Phosphopeptides / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D018909:src Homology Domains
D000952:Antigens, Polyomavirus Transforming; D008024:Ligands; D010748:Phosphopeptides; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor