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An electrostatic network and long‐range regulation of Src kinases
Author(s) -
Ozkirimli Elif,
Yadav Shalini S.,
Miller W. Todd,
Post Carol Beth
Publication year - 2008
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.037457.108
Subject(s) - allosteric regulation , sh3 domain , sh2 domain , biophysics , chemistry , proto oncogene tyrosine protein kinase src , phosphorylation , allosteric enzyme , kinase , enzyme kinetics , hamp domain , tyrosine protein kinase csk , molecular dynamics , protein structure , active site , biochemistry , enzyme , binding site , binding domain , biology , computational chemistry
The regulatory mechanism of Src tyrosine kinases includes conformational activation by a change in the catalytic domain tertiary structure and in domain–domain contacts between the catalytic domain and the SH2/SH3 regulatory domains. The kinase is activated when tyrosine phosphorylation occurs on the activation loop, but without phosphorylation of the C‐terminal tail. Activation also occurs by allostery when contacts between the catalytic domain (CD) and the regulatory SH3 and SH2 domains are released as a result of exogenous protein binding. The aim of this work is to examine the proposed role of an electrostatic network in the conformational transition and to elucidate the molecular mechanism for long‐range, allosteric conformational activation by using a combination of experimental enzyme kinetics and nonequilibrium molecular dynamics simulations. Salt dependence of the induction phase is observed in kinetic assays and supports the role of an electrostatic network in the transition. In addition, simulations provide evidence that allosteric activation involves a concerted motion coupling highly conserved residues, and spanning several nanometers from the catalytic site to the regulatory domain interface to communicate between the CD and the regulatory domains.