GroEL/GroES: Structure and Function of a Two-Stroke Folding Machine

Abstract

Recent structural and functional studies have greatly advanced our understanding of the mechanism by which chaperonins (Cpn60) mediate protein folding, the final step in the accurate expression of genetic information.Escherichia coliGroEL has a symmetric double-toroid architecture, which binds nonnative polypeptide substrates on the hydrophobic walls of its central cavity. The asymmetric binding of ATP and cochaperonin GroES to GroEL triggers a major conformational change in thecisring, creating an enlarged chamber into which the bound nonnative polypeptide is released. The structural changes that create thecisassembly also change the lining of the cavity wall from hydrophobic to hydrophilic, conducive to folding into the native state. ATP hydrolysis in thecisring weakens it and primes the release of products. When ATP and GroES bind to thetransring, it forms a stronger assembly, which disassembles theciscomplex through negative cooperativity between rings. The opposing function of the two rings operates as if the system had two cylinders, one expelling the products of the reaction as the other loads up the reactants. One cycle of the reaction gives the polypeptide about 15 s to fold at the cost of seven ATP molecules. For some proteins, several cycles of GroEL assistance may be needed in order to achieve their native states.