Multivalent protein-protein interactions are pivotal regulators of eukaryotic Hsp70 complexes

Cell Stress Chaperones. 2022 Jul;27(4):397-415. doi: 10.1007/s12192-022-01281-1. Epub 2022 Jun 7.


Heat shock protein 70 (Hsp70) is a molecular chaperone and central regulator of protein homeostasis (proteostasis). Paramount to this role is Hsp70's binding to client proteins and co-chaperones to produce distinct complexes, such that understanding the protein-protein interactions (PPIs) of Hsp70 is foundational to describing its function and dysfunction in disease. Mounting evidence suggests that these PPIs include both "canonical" interactions, which are universally conserved, and "non-canonical" (or "secondary") contacts that seem to have emerged in eukaryotes. These two categories of interactions involve discrete binding surfaces, such that some clients and co-chaperones engage Hsp70 with at least two points of contact. While the contributions of canonical interactions to chaperone function are becoming increasingly clear, it can be challenging to deconvolute the roles of secondary interactions. Here, we review what is known about non-canonical contacts and highlight examples where their contributions have been parsed, giving rise to a model in which Hsp70's secondary contacts are not simply sites of additional avidity but are necessary and sufficient to impart unique functions. From this perspective, we propose that further exploration of non-canonical contacts will generate important insights into the evolution of Hsp70 systems and inspire new approaches for developing small molecules that tune Hsp70-mediated proteostasis.

Keywords: Bag domain; Hsp110; J-domain protein; Nucleotide exchange factor; Protein aggregation; Protein folding.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Eukaryota*
  • HSP110 Heat-Shock Proteins / metabolism
  • HSP70 Heat-Shock Proteins* / metabolism
  • Humans
  • Molecular Chaperones / metabolism
  • Protein Binding
  • Protein Folding


  • HSP110 Heat-Shock Proteins
  • HSP70 Heat-Shock Proteins
  • Molecular Chaperones