Abstract
AbstractAllosteric regulation, i. e. the control exerted on an orthosteric site by an effector interacting at a distinct and distant site, represents a prime example of a precise tuning system of several key biological processes like gene transcription, cell adhesion and, most importantly, signal transduction. Since its discovery sixty years ago, the molecular mechanisms underlying this phenomenon have been extensively investigated. The aim of this minireview is to introduce the reader to the topic of protein allostery. In particular, we briefly overview the allosteric models postulated over the years and we describe the most relevant chemical and biophysical approaches reported so far for the identification of putative allosteric sites and/or for the investigation of allosteric signal propagation throughout the protein. An outlook of the main computational and experimental methods is followed by four case studies representative of different proteins classes: enzymes, hub proteins, cell receptors, and intrinsically disordered proteins.
Highlights
Allosteric regulation of proteins plays a pivotal role in a variety of biological processes, such as enzymatic activity, cell adhesion, signal transduction and transcriptional regulation
An attempt in this direction is represented by the two conceptual models Conformational Selection (CS, or population shift) and Induced Fit (IF, or reaction front mechanism) (Figure 1).[3]
From a computational point of view, software for allosteric site prediction have been developed, along with accessible databases of known allosteric modulators, while Molecular Dynamics (MD) trajectories can be perused from different angles to detect signal propagation pathways
Summary
Allosteric regulation of proteins plays a pivotal role in a variety of biological processes, such as enzymatic activity, cell adhesion, signal transduction and transcriptional regulation. Monod[1] and Koshland[2] pioneered the studies on the cooperativity of oxygen binding to oligomeric haemoglobin in the 1960s, setting for decades the benchmark with their symmetric[1] (or MWC, Monod-Wyman-Changeux) and sequential[2] (or KNF, Koshland-Nemethy-Filmer) models, respectively Both models provide a phenomenological qualitative description of two well-defined end-point structures at different energy levels Tensed (T) and Relaxed (R)), tightly linking allostery to conformational change but lacking an explanation on how the information is propagated from one site to the other An attempt in this direction is represented by the two conceptual models Conformational Selection (CS, or population shift) and Induced Fit (IF, or reaction front mechanism) (Figure 1).[3] In the case of conformational selection, the protein exists in equilibrium between an active (A) and an inactive (I) state even in the absence of the ligand (L, Figure 1). Both mechanisms can take place depending on the ligand concentration and the free energy differences among the two states.[3]
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