Hsp70 molecular chaperones mediate a wide array of biological functions by binding to incompletely folded substrate proteins or to regions of protein substrates that are unfolded and accessible. Binding to Hsp70 chaperones displays selective promiscuity in that some sequences that meet the criterion of accessibility and conformational flexibility are favored over others, while in the cell, a given Hsp70 chaperone has the capacity to bind many different substrates. Analyses of the binding preferences of Hsp70 chaperones have led to predictive scoring algorithms that reproduce quite well the experimentally derived binding preferences determined from peptide arrays (Rudiger, S., et al., EMBO J. 16, 1501 [1997]; Van Durme, J., et al., PLoS Comp. Biol. e1000475 [2009]). Still, major questions remain about how Hsp70 chaperones bind full-length protein substrates, and we lack details regarding the mode of binding to a particular sequence. We have been using a model unfolded substrate, the precursor to alkaline phosphatase, to explore Hsp70 binding modes. We seek a detailed understanding of the basis for selectivity of one binding site over another as well as the promiscuity of the chaperone, which enables it to bind many different protein substrates, as demanded by its physiological roles. We have learned that the binding cleft of the bacterial Hsp70, DnaK, has pockets with different degrees of plasticity, such that peptide substrates can utilize the pockets to accommodate different residue types, thus enabling sequence promiscuity. Other pockets are more restrictive and contribute to the selectivity of peptide binding. Major questions remain about the involvement of regions beyond the canonical binding cleft in binding to substrate proteins. These and other aspects of substrate/Hsp70 interaction will be discussed.

<b>Award Address</b> (Ralph F. Hirschmann Award in Peptide Chemistry sponsored by the Merck Research Laboratories). When peptides mimic proteins, and when they do not: Promiscuous selectivity in Hsp70 chaperone binding of substrates

255th National Meeting (2018)

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Award Address (Ralph F. Hirschmann Award in Peptide Chemistry sponsored by the Merck Research Laboratories). When peptides mimic proteins, and when they do not: Promiscuous selectivity in Hsp70 chaperone binding of substrates