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

doi:10.1021/bi034353x

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

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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 language	English
Pages (from-to)	11120-11127
Number of pages	8
Journal	Biochemistry
Volume	42
DOIs	https://doi.org/10.1021/bi034353x
Publication status	Published - 30 Sept 2003

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title = "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",

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.",

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T1 - 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

AU - Gunther, Ulrich

AU - Weyrauch, B

AU - Zhang, X

AU - Schaffhausen, B

PY - 2003/9/30

Y1 - 2003/9/30

N2 - 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.

AB - 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.

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EP - 11127

JO - Biochemistry

JF - Biochemistry

ER -

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

Abstract

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