Jean-Pierre Changeux' PhD and the origins of allostery

Jean-Pierre Changeux Download Jean-Pierre Changeux's PhD thesis

During his PhD training, under the direction of Jacques Monod and Francois Jacob, Jean-Pierre Changeux studied the regulations of enzymes by compounds different from their substrates. This work led to the concept of allosteric regulations, that is regulations taking place between to distant sites of the proteins. This work was published in two articles and a review:

Changeux J.-P. (1961). The feedback control mechanism of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harbor. Symp. Quant. Biol. 26: 313-318.

Changeux J.-P. (1963). Allosteric Interactions on biosynthetic L-theonine deaminase from E. coli K12. Cold Spring Harb Symp Quant Biol, 28: 497-504

Monod J., Changeux J.-P., and Jacob. F. (1963). Allosteric proteins and cellular control systems. J. Mol. Biol. 6: 306-329

The experimental work presented in the papers and the thesis was instrumental to the development of the model of concerted transitions for allosteric proteins.

Monod J., Wyman J., and Changeux J.-P. (1965). On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12: 88-118.

The main ideas behind this theory are: 1) proteins can exist under various conformations in thermal equilibrium in the absence of regulators. The allosteric regulators merely shift the equilibrium between the conformations, stabilizing the ones for which they display the highest affinity, and 2) all the subunits of a symmetrical multimeric protein exist in the same conformation, the transition taking place in a concerted fashion. The resulting model explain the observed cooperativity without a progressive change of biophysical parameters. More about the MWV model can be found in a blog post.

In his PhD thesis, Changeux also suggested that the recognition and transmission of signals by membrane, and in particular by synapses, could use the same mechanisms than the allosteric regulations of enzymes. More than forty years of research would follow, mainly focussed on nicotinic acetylcholine receptors.