Allosteric landscapes of eukaryotic cytoplasmic Hsp70s are shaped by evolutionary tuning of key interfaces.

摘要: The 70-kDa heat shock proteins (Hsp70s) are molecular chaperones that perform a wide range of critical cellular functions. They assist in the folding newly synthesized proteins, facilitate assembly specific protein complexes, shepherd across membranes, and prevent misfolding aggregation. Hsp70s these functions by conserved mechanism relies on allosteric cycles nucleotide-modulated binding release client proteins. Current models for Hsp70 allostery have come from extensive study bacterial Hsp70, DnaK. Extending our understanding to eukaryotic is extremely important not only providing likely common mechanistic framework but also because their central roles physiology. In this study, we examined behaviors cytoplasmic Hsp70s, HspA1 Hsc70, found significant differences We Hsc70 favor state which nucleotide-binding domain (NBD) substrate-binding (SBD) intimately docked significantly more as compared Past work established NBD-SBD interface helical lid-β-SBD govern landscape Here, identified sites interfaces differ between Our mutational analysis has revealed key evolutionary variations account population shifts undocked conformations. These results underline tunability modulation through diversification suggest where small-molecule modulators could influence function.