Forces Driving Chaperone Action.
It is still unclear what molecular forces drive chaperone-mediated protein folding. Here, we obtain a detailed mechanistic understanding of the forces that dictate the four key steps of chaperone-client interaction: initial binding, complex stabilization, folding, and release. Contrary to the common belief that chaperones recognize unfolding intermediates by their hydrophobic nature, we discover that the model chaperone Spy uses long-range electrostatic interactions to rapidly bind to its unfolded client protein Im7. Short-range hydrophobic interactions follow, which serve to stabilize the complex. Hydrophobic collapse of the client protein then drives its folding. By burying hydrophobic residues in its core, the client's affinity to Spy decreases, which causes client release. By allowing the client to fold itself, Spy circumvents the need for client-specific folding instructions. This mechanism might help explain how chaperones can facilitate the folding of various unrelated proteins.
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Philipp
P
Koldewey
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Frederick
F
Stull
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Scott
S
Horowitz
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Raoul
R
Martin
Department of Molecular, Cellular and Developmental Biology, and the Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: jbardwel@umich.edu.
James C A
JCA
Bardwell
D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D019277:Entropy; D004926:Escherichia coli / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D018832:Molecular Chaperones / Q000378:metabolism*; D019897:Periplasm / Q000737:chemistry; D033903:Periplasmic Proteins / Q000378:metabolism*; D017510:Protein Folding; D055672:Static Electricity
D002352:Carrier Proteins; C509253:E colicin-binding immunity protein Im7, E coli; D029968:Escherichia coli Proteins; D018832:Molecular Chaperones; D033903:Periplasmic Proteins; C104888:Spy protein, E coli