Dynamics-Driven Allostery in Protein Kinases. Issue 11 (November 2015)

• Record Type: Journal Article
• Authors: Kornev, Alexandr P.; Taylor, Susan S.
• Is Part Of: Trends in biochemical sciences. Volume 40:Issue 11(2015)
• Page Start: 628
• Page End: 647
• Publication Date: 2015-11
• Subjects: protein kinases -- allostery -- protein dynamics -- community analysis; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2015.09.002
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : Protein kinases have very dynamic structures and their functionality strongly depends on their dynamic state. Active kinases reveal a dynamic pattern with residues clustering into semirigid communities that move in μs–ms timescale. Previously detected hydrophobic spines serve as connectors between communities. Communities do not follow the traditional subdomain structure of the kinase core or its secondary structure elements. Instead they are organized around main functional units. Integration of the communities depends on the assembly of the hydrophobic spine and phosphorylation of the activation loop. Single mutations can significantly disrupt the dynamic infrastructure and thereby interfere with long-distance allosteric signaling that propagates throughout the whole molecule. Dynamics is proposed to be the underlying mechanism for allosteric regulation in protein kinases. Trends: Protein kinase allostery is based on changes in dynamics of large ensembles of residues that emerge stochastically inside the protein. Active kinases are in a particular dynamic mode that is characterized by an ATP-dependent μs–ms timescale that radiates across the molecule. The protein kinase core consists of groups of residues (communities) that move as semi-rigid bodies and correlate with catalytic and regulatory functions. Non-conserved elements are integrated with the core communities and are essential for the dynamic regulation of the core. Assembly of the active kinase, as defined by the integrated communities, is mediated by the assembly of the regulatory spine and is often facilitated by activation loop phosphorylation. Dynamics mediate the classic connection between a protein structure and its function even when major conformational changes are not apparent.