28 April 2017
Fox Chase Cancer Center
About 15 years ago, we stumbled upon a disease-associated missense variant of an essential human enzyme that had unexpected kinetic and biophysical properties. Through the next decade we determined that this enzyme exists as an equilibrium among architecturally distinct assemblies. The interconversion between the assemblies forms a physiologically relevant basis for allosteric regulation. More surprisingly, the multimers must dissociate, change shape, and reassemble as part of the allosteric process. Thus arose the definition of the morpheein model of protein allostery, illustrated pictorially below:
A key lesson remains how this discovery could easily have been overlooked as experimental artifact based on the "one sequence, one structure, one function" dogma that continues to predominate our analysis of the growing protein sequence and protein crystal structure databases. The effect of reversible multimerization equilibria between properly folded, but alternately assembled proteins has long been overlooked as another of Nature's tricks to optimize functional diversity from a limited genome. In the well characterized examples, the conformational change in the dissociated state is a hinge motion between two folded domains of each subunit.
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