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

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  • Wenli Meng
    Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003;
  • Eugenia M. Clerico
    Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003;
  • Natalie McArthur
    Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003;
  • Lila M. Gierasch
    Department of Biochemistry and Molecular Biology, University of Massachusetts Amherst, Amherst, MA 01003;

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<jats:title>Significance</jats:title> <jats:p>Heat shock protein 70 (Hsp70) molecular chaperones act as a central hub of cellular proteostasis network. The functions of Hsp70s rely on allosteric communication between nucleotide-binding domain and substrate-binding domain. Current mechanistic models for Hsp70 allostery are based on extensive study of the bacterial Hsp70, DnaK. Here, we report that the allosteric landscapes of the eukaryotic cytoplasmic Hsp70s, HspA1 and Hsc70, diverge significantly from that of DnaK in that they favor a domain-docked, low substrate-affinity state much more than DnaK does. Our mutational results illustrate how this evolutionary tunability of Hsp70s arises by modulation of key allosteric interfaces. These insights will help in understanding the mechanism of Hsp70 functional diversities and aid in the design of small-molecule modulators of Hsp70s.</jats:p>

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