Structural and Kinetic Views of Molecular Chaperones in Multidomain Protein Folding

Abstract

Despite recent developments in protein structure prediction, the process of the structure formation, folding, remains poorly understood. Notably, folding of multidomain proteins, which involves multiple steps of segmental folding, is one of the biggest questions in protein science. Multidomain protein folding often requires the assistance of molecular chaperones. Molecular chaperones promote or delay the folding of the client protein, but the detailed mechanisms are still unclear. This review summarizes the findings of biophysical and structural studies on the mechanism of multidomain protein folding mediated by molecular chaperones and explains how molecular chaperones recognize the client proteins and alter their folding properties. Furthermore, we introduce several recent studies that describe the concept of kinetics–activity relationships to explain the mechanism of functional diversity of molecular chaperones.

Enzymatic and synthetic regulation of polypeptide folding

“…Thus, the effects of the molecular chaperones on the folding of client proteins are determined by the balance between the binding kinetics and intrinsic folding rate of the client protein. 63 This kinetics-activity relationship is consistent with the "kinetic partitioning" theory proposed in the 1990s to explain the mechanism of selection of the client protein of SecB for the secretary pathway. 23 As indicated by the examples described above, recognition of the sequence of the client protein by molecular chaperones is promiscuous, whereas the kinetic properties are variable.…”

“…Thus, the effects of the molecular chaperones on the folding of client proteins are determined by the balance between the binding kinetics and intrinsic folding rate of the client protein. 63 …”