Allosteric Mechanisms of Signal Transduction

  title={Allosteric Mechanisms of Signal Transduction},
  author={Jean Pierre Changeux and Stuart J. Edelstein},
  pages={1424 - 1428}
Forty years ago, a simple model of allosteric mechanisms (indirect interactions between distinct sites), used initially to explain feedback-inhibited enzymes, was presented by Monod, Wyman, and Changeux. We review the MWC theory and its applications for the understanding of signal transduction in biology, and also identify remaining issues that deserve theoretical and experimental substantiation. 

The structural basis of allosteric regulation in proteins

Direct observation in solution of a preexisting structural equilibrium for a mutant of the allosteric aspartate transcarbamoylase

The cooperative binding of aspartate in as partate transcarbamoylase appears to result from the combination of the preexisting quaternary structure equilibrium with local changes induced by CP binding, a central postulate of the Monod, Wyman, and Changeux model.

Allosteric mechanisms can be distinguished using structural mass spectrometry

It is demonstrated that structural MS offers a way to break this impasse by providing the full distribution of ligand-bound states of a protein complex, and it is possible to determine all the binding constants of a ligand to a highly multimeric cooperative system, and thereby infer its allosteric mechanism.

Allosteric modulation as a unifying mechanism for receptor function and regulation

Four major receptor families enable cells to respond to chemical and physical signals from their proximal environment, and recent studies point to common mechanisms governing the allosteric transitions of these receptors, including the impact of oligomerization, pre‐existing and functionally distinct conformational ensembles, intrinsically disordered regions, and the occurrence ofallosteric modulatory sites.

Allosteric Mechanism of Pyruvate Kinase from Leishmania mexicana Uses a Rock and Lock Model*

The results presented here illustrate how conformational changes coupled with effector binding correlate with loss of flexibility and increase in thermal stability providing a general mechanism for allosteric control.

Allosteric regulation of pentameric ligand-gated ion channels

The present results suggest that ion gating involves a large structural reorganization of the molecule mediated by two distinct quaternary transitions, a global twisting and the blooming of the extracellular domain, which can be modulated by ligand binding at the topographically distinct orthosteric and allosteric sites.

Computational approaches to investigating allostery.

Structural identification of the pathway of long-range communication in an allosteric enzyme

The crystal structure of the thrombin-PAR1 complex, solved at 2.2-Å resolution, reveals the details of this long-range allosteric communication in terms of a network of polar interactions.



Allosteric proteins and cellular control systems.

On the cooperativity of biological membranes.

The Monod-Wyman-Changeux of allosteric transitions in enzyme-substrate reactions to a membrane composed of identical units (protomers) is extended and it appears possible to have a first-order phase transition when the chemical potential of the substrate is varied, holding the temperature constant.

Extensions of the Allosteric Model for Haemoglobin

Numerical analysis yields a unique value for the allosteric constant showing that only the two state model can account for the behaviour of the protein.

Conformational spread: The propagation of allosteric states in large multiprotein complexes

  • D. BrayT. Duke
  • Biology
    Annual review of biophysics and biomolecular structure
  • 2004
It is suggested that conformational spread could provide the basis of a solid-state «circuitry» in a living cell, able to integrate biochemical and biophysical events over hundreds of protein molecules.

G Protein-Coupled Receptor Dimerization: Function and Ligand Pharmacology

  • G. Milligan
  • Biology, Chemistry
    Molecular Pharmacology
  • 2004
Key questions that remain to be addressed effectively include the prevalence and relevance of these in native tissues and the implications of heterodimerization for pharmacology and, potentially, for drug design.

New insights into allosteric mechanisms from trapping unstable protein conformations in silica gels.

To understand why the classical two-state allosteric model of Monod, Wyman, and Changeux explains cooperative oxygen binding by hemoglobin but does not explain changes in oxygen affinity by

Molecular model of a lattice of signalling proteins involved in bacterial chemotaxis

The proposed structure is a regular two-dimensional lattice in which the cytoplasmic ends of chemotactic-receptor dimers are inserted into a hexagonal array of CheA and CheW molecules, which creates separate compartments for adaptation and downstream signalling, and indicates a possible basis for the spread of activity within the cluster.