Dataset Information

Dynamic Allostery in PLC?1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR.

ABSTRACT: Phosphatidylinositol phospholipase C? (PLC?) is an intracellular membrane-associated second-messenger signaling protein activated by tyrosine kinases such as fibroblast growth factor receptor 1. PLC? contains the regulatory ?-specific array (?SA) comprising a tandem Src homology 2 (SH2) pair, an SH3 domain, and a split pleckstrin homology domain. Binding of an activated growth factor receptor to ?SA leads to Tyr783 phosphorylation and consequent PLC? activation. Several disease-relevant mutations in ?SA have been identified; all lead to elevated phospholipase activity. In this work, we describe an allosteric mechanism that connects the Tyr783 phosphorylation site to the nSH2-cSH2 junction and involves dynamic interactions between the cSH2-SH3 linker and cSH2. Molecular dynamics simulations of the tandem SH2 protein suggest that Tyr783 phosphorylation is communicated to the nSH2-cSH2 junction by modulating cSH2 binding to sections of the cSH2-SH3 linker. NMR chemical shift perturbation analyses for designed tandem SH2 constructs reveal combined fast and slow dynamic processes that can be attributed to allosteric communication involving these regions of the protein, establishing an example in which complex N-site exchange can be directly inferred from 1H,15N-HSQC spectra. Furthermore, in tandem SH2 and ?SA constructs, molecular dynamics and NMR results show that the Arg687Trp mutant in PLC?1 (equivalent to the cancer mutation Arg665Trp in PLC?2) perturbs the dynamic allosteric pathway. This combined experimental and computational study reveals a rare example of multistate kinetics involved in a dynamic allosteric process that is modulated in the context of a disease-relevant mutation. The allosteric influences and the weakened binding of the cSH2-SH3 linker to cSH2 should be taken into account in any more holistic investigation of PLC? regulation.

SUBMITTER: Koss H

PROVIDER: S-EPMC6035297 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Dynamic Allostery in PLCγ1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR.

Koss Hans H Bunney Tom D TD Esposito Diego D Martins Marta M Katan Matilda M Driscoll Paul C PC

Biophysical journal 20180701 1

Phosphatidylinositol phospholipase Cγ (PLCγ) is an intracellular membrane-associated second-messenger signaling protein activated by tyrosine kinases such as fibroblast growth factor receptor 1. PLCγ contains the regulatory γ-specific array (γSA) comprising a tandem Src homology 2 (SH2) pair, an SH3 domain, and a split pleckstrin homology domain. Binding of an activated growth factor receptor to γSA leads to Tyr783 phosphorylation and consequent PLCγ activation. Several disease-relevant mutation ...[more]

PMID: 29972810

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Dataset Information

Dynamic Allostery in PLC?1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR.

Publications

Dynamic Allostery in PLCγ1 and Its Modulation by a Cancer Mutation Revealed by MD Simulation and NMR.

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