Structural Instability Tuning as a Regulatory Mechanism in Protein-Protein Interactions

• DOI: 10.1016/j.molcel.2011.09.022
• Publication Date: 2011-12-11T04:26:24Z
• Authors: Li Chen; Vassilia Balabanidou; David P. Remeta; Conceição A.S.A. ...; Athina G. Portaliou; Anastassios Economou; Charalampos G. Ka...
• Keywords: Models, Molecular; 0301 basic medicine; Protein Folding; Protein Conformation; Protein Stability; Escherichia coli Proteins; Molecular Mimicry; Proteins; Cell Biology; Evolution, Molecular; 03 medical and health sciences; Protein Multimerization; Molecular Biology; Molecular Chaperones; Protein Binding

Protein-protein interactions mediate a vast number of cellular processes. Here, we present a regulatory mechanism in protein-protein interactions mediated by finely tuned structural instability and coupled with molecular mimicry. We show that a set of type III secretion (TTS) autoinhibited homodimeric chaperones adopt a molten globule-like state that transiently exposes the substrate binding site as a means to become rapidly poised for binding to their cognate protein substrates. Packing defects at the homodimeric interface stimulate binding, whereas correction of these defects results in less labile chaperones that give rise to nonfunctional biological systems. The protein substrates use structural mimicry to offset the weak spots in the chaperones and to counteract their autoinhibitory conformation. This regulatory mechanism of protein activity is evolutionarily conserved among several TSS systems and presents a lucid example of functional advantage conferred upon a biological system by finely tuned structural instability.