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Accelerated Communication

An electrostatic network and long-range regulation of Src kinases

¹ Bogazici University;
² SUNY at Stony Brook;
³ Purdue University

(RECEIVED July 11, 2008; ACCEPTED July 30, 2008)

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 a combination of experimental enzyme kinetics and non-equilibrium molecular dynamics simulations. A 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 nm from the catalytic site to the regulatory domain interface for communication between CD and the regulatory domains.

Keywords: Structure/function studies; Computational Analysis of Protein Structure; Molecular mechanics/dynamics; allostery; salt dependence; tyrosine phosphorylation

⁴ E-mail: cbp{at}purdue.edu

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