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.
Highlights
Significant advances in protein structure prediction have led to the easy availability of protein structural information [1,2]
We focus on multidomain protein folding, assisted by molecular chaperones, and discuss how molecular chaperones alter the folding properties of client proteins
The segmental folding of the multidomain protein, dihydrofolate reductase (DHFR), which is composed of two domains, has been supported using molecular dynamics (MD) simulation studies [30]
Summary
Significant advances in protein structure prediction have led to the easy availability of protein structural information [1,2]. Protein folding has been traditionally studied on small single-domain proteins, including BPTI [6], ribonuclease [7], and cytochrome c [8,9] These studies have provided structural insights into folding intermediates and, have expanded the understanding of the major folding pathways. One chaperone can work as a foldase for one group and as a holdase for another group of client proteins This activity switching of molecular chaperones is believed to be important in regulating the folding of multidomain proteins. This review summarizes fundamental understanding and recent advances in multidomain protein folding and mechanistic insights into molecular chaperones. Recent advances in structural biology in understanding how molecular chaperones recognize unfolded client proteins are discussed. A combination of structural and kinetic information of the chaperone–client complex explains the distinct and variable activities of molecular chaperones
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