NMR insights into protein allostery

Abstract

Allosterism is one of nature's principal methods for regulating protein function. Allosterism utilizes ligand binding at one site to regulate the function of the protein by modulating the structure and dynamics of a distant binding site. In this review, we first survey solution NMR techniques and how they may be applied to the study of allostery. Subsequently, we describe several examples of application of NMR to protein allostery and highlight the unique insight provided by this experimental technique.

Role of protein dynamics in ion selectivity and allosteric coupling in the NaK channel

“…3B and 4B). Motion on this timescale is often correlated with exchange between functional states in the case of enzymes (35). Although we cannot currently assign the conformational exchange process to functional states of the channel, we note that the residues sensing motion are localized to the regions of NaK that would change environment upon channel opening/closing.…”

Chaperones and chaperone–substrate complexes: Dynamic playgrounds for NMR spectroscopists

“…The chemical shift perturbations induced by close spatial contacts and direct conformational changes can be large in magnitude, and localize around the ligand-binding pocket or at the protein-binding interface. In addition, allosteric effects resulting from indirect conformational changes of the protein are typically observed distant from the binding pocket or interface [88,89].…”

The role of protein dynamics in allosteric effects—introduction

“…In the last few years, there have been a number of reports describing clear roles for protein dynamics in allosteric effects, both in the transitions between states and in making substantial contributions to the thermodynamics of the allosteric effect itself (Jiao et al 2012;Kern and Zuiderweg 2003;Law et al 2014;Manley and Loria 2012;McElroy et al 2002;Palazzesi et al 2013;Popovych et al 2006;Rivalta et al 2012;Shi and Kay 2014;Stevens et al 2001). (It is of course difficult to demonstrate the existence of allosteric effects produced solely by changes in dynamics, since the failure to observe a structural change does not mean that it does not occur; Nussinov and Tsai 2014.…”

“…Secondly, such effects are clearly not restricted to small molecule ligands-allosteric effects involving the binding of other macromolecules or covalent modification (such as phosphorylation) are of fundamental importance in the regulation of signal transduction and of metabolism. Thirdly, the concept of population shifts between pre-existing states, the basis of the MWC model, has been discussed more broadly within the 'energy landscape' or 'ensemble' formalism (Frauenfelder et al 1991;Hilser et al 2012;Itoh and Sasai 2010;Motlagh et al 2014) and has also come to the fore thanks to the recent development of NMR methods for detecting and characterising conformational states present in low populations (Baldwin and Kay 2009;Manley and Loria 2012;Mittermaier and Kay 2006;Sekhar and Kay 2013).…”