Controlling Allosteric Networks in Proteins

Abstract

Allosteric transition, defined as conformational changes induced by ligand binding, is one of the fundamental properties of proteins. Allostery has been observed and characterized in many proteins, and has been recently utilized to control protein function via regulation of protein activity. Here, we review the physical and evolutionary origin of protein allostery, as well as its importance to protein regulation, drug discovery, and biological processes in living systems. We describe recently developed approaches to identify allosteric pathways, connected sets of pairwise interactions that are responsible for propagation of conformational change from the ligand-binding site to a distal functional site. We then present experimental and computational protein engineering approaches for control of protein function by modulation of allosteric sites. As an example of application of these approaches, we describe a synergistic computational and experimental approach to rescue the cystic-fibrosis-associated protein cystic fibrosis transmembrane conductance regulator, which upon deletion of a single residue misfolds and causes disease. This example demonstrates the power of allosteric manipulation in proteins to both elucidate mechanisms of molecular function and to develop therapeutic strategies that rescue those functions. Allosteric control of proteins provides a tool to shine a light on the complex cascades of cellular processes and facilitate unprecedented interrogation of biological systems.

Structural basis for KCNE3 modulation of potassium recycling in epithelia

“…This seems unlikely, suggesting that the energy coupling between the KCNQ1 and KCNE3 residue pairs documented in the double-mutant cycle studies ( 26 , 27 ) involves allosteric networks rather than direct contact. The allosteric coupling of distal residues is a well-established phenomenon in protein science ( 34 ). …”

Decomposing Dynamical Couplings in Mutated scFv Antibody Fragments into Stabilizing and Destabilizing Effects

“…11,13,14–16 The ensemble nature of allosteric response encompasses a continuum of cooperative processes that involve protein dynamics with, and without, persistent conformational change. 17 Dynamic allostery 18–23 occurs when dynamic fluctuations are altered without conformational change.…”

Allosteric Transmission along a Loosely Structured Backbone Allows a Cardiac Troponin C Mutant to Function with Only One Ca2+ Ion

“…An understanding of how Ca 2ϩ -binding proteins change during evolution, preserving (or losing) their ability to regulate biological function, can provide information for the engineering of new molecules. Also, targeting this allosteric mechanism seems uniquely suited to the task of exploring the dynamics and activity of these Ca 2ϩ sensors (37)(38)(39).…”