title: How hsp70 molecular machines interact with their substrates to mediate diverse physiological functions.
abstract: Hsp70 molecular chaperones are implicated in a wide variety of cellular processes, including protein biogenesis, protection of the proteome from stress, recovery of proteins from aggregates, facilitation of protein translocation across membranes, and more specialized roles such as disassembly of particular protein complexes. It is a fascinating question to ask how the mechanism of these deceptively simple molecular machines is matched to their roles in these wide-ranging processes. The key is a combination of the nature of the recognition and binding of Hsp70 substrates and the impact of Hsp70 action on their substrates. In many cases, the binding, which relies on interaction with an extended, accessible short hydrophobic sequence, favors more unfolded states of client proteins. The ATP-mediated dissociation of the substrate thus releases it in a relatively less folded state for downstream folding, membrane translocation, or hand-off to another chaperone. There are cases, such as regulation of the heat shock response or disassembly of clathrin coats, however, where binding of a short hydrophobic sequence selects conformational states of clients to favor their productive participation in a subsequent step. This Perspective discusses current understanding of how Hsp70 molecular chaperones recognize and act on their substrates and the relationships between these fundamental processes and the functional roles played by these molecular machines.
authors: Department of Biochemistry and Molecular Biology and Department of Chemistry, Life Sciences Laboratory, University of Massachusetts Amherst, 240 Thatcher Way, Amherst, MA 01003, USA.
authors: Eugenia M
authors: EM
authors: Clerico
authors: Department of Biochemistry and Molecular Biology and Department of Chemistry, Life Sciences Laboratory, University of Massachusetts Amherst, 240 Thatcher Way, Amherst, MA 01003, USA.
authors: Joseph M
authors: JM
authors: Tilitsky
authors: Department of Biochemistry and Molecular Biology and Department of Chemistry, Life Sciences Laboratory, University of Massachusetts Amherst, 240 Thatcher Way, Amherst, MA 01003, USA.
authors: Wenli
authors: W
authors: Meng
authors: Department of Biochemistry and Molecular Biology and Department of Chemistry, Life Sciences Laboratory, University of Massachusetts Amherst, 240 Thatcher Way, Amherst, MA 01003, USA. Electronic address: gierasch@biochem.umass.edu.
authors: Lila M
authors: LM
authors: Gierasch
mesh_terms: D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D020836:Protein Structure, Quaternary; D058767:Protein Unfolding
chemical_list: D018840:HSP70 Heat-Shock Proteins; D008024:Ligands
keywords: Hsp70 molecular chaperone; chaperone substrates; complex disassembly; disaggregation; protein folding