Promiscuous binding by Hsp70 results in conformational heterogeneity and fuzzy chaperone-substrate ensembles

eLife

Ashok Sekhar¹  Jayashree Nagesh²  Lewis E Kay³  Rina Rosenzweig⁴ 

[1] Department of Biochemistry, The University of Toronto, Toronto, Canada;Department of Chemistry, University of Toronto, Toronto, Canada;Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel;Department of Molecular Genetics, The University of Toronto, Toronto, Canada;

关键词: Hsp70;    conformational heterogeneity;    methyl-TROSY NMR;    molecular chaperones;    protein folding;   

DOI  :  10.7554/eLife.28030

来源: DOAJ

【 摘 要 】

The Hsp70 chaperone system is integrated into a myriad of biochemical processes that are critical for cellular proteostasis. Although detailed pictures of Hsp70 bound with peptides have emerged, correspondingly detailed structural information on complexes with folding-competent substrates remains lacking. Here we report a methyl-TROSY based solution NMR study showing that the Escherichia coli version of Hsp70, DnaK, binds to as many as four distinct sites on a small 53-residue client protein, hTRF1. A fraction of hTRF1 chains are also bound to two DnaK molecules simultaneously, resulting in a mixture of DnaK-substrate sub-ensembles that are structurally heterogeneous. The interactions of Hsp70 with a client protein at different sites results in a fuzzy chaperone-substrate ensemble and suggests a mechanism for Hsp70 function whereby the structural heterogeneity of released substrate molecules enables them to circumvent kinetic traps in their conformational free energy landscape and fold efficiently to the native state.

【 授权许可】

Unknown