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BIOLOGICAL SCIENCES / BIOPHYSICS
Coupling between allosteric transitions in GroEL and assisted folding of a substrate protein
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*Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; and Biophysics Program, Institute for Physical Science and Technology, and Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742
Edited by Harold A. Scheraga, Cornell University, Ithaca, NY, and approved March 27, 2007 (received for review January 22, 2007)
Escherichia coli chaperonin, GroEL, helps proteins fold under nonpermissive conditions. During the reaction cycle, GroEL undergoes allosteric transitions in response to binding of a substrate protein (SP), ATP, and the cochaperonin GroES. Using coarse-grained representations of the GroEL and GroES structures, we explore the link between allosteric transitions and the folding of a model SP, a de novo-designed four-helix bundle protein, with low spontaneous yield. The ensemble of GroEL-bound SP is less structured than the bulk misfolded structures. Upon binding, which kinetically occurs in two stages, the SP loses not only native tertiary contacts but also experiences a decrease in helical content. During multivalent binding and the subsequent ATP-driven transition of GroEL the SP undergoes force-induced stretching. Upon encapsulation, which occurs upon GroES binding, the SP finds itself in a "hydrophilic" cavity in which it can reach the folded conformation. Surprisingly, we find that the yield of the native state in the expanded GroEL cavity is relatively small even after it remains in it for twice the spontaneous folding time. Thus, in accord with the iterative annealing mechanism, multiple rounds of binding, partial unfolding, and release of the SP are required to enhance the yield of the folded SP.
native state yield | soft nanomachine | force-induced stretching
Present address: Department of Chemistry, University of Cincinnati, P.O. Box 210172, Cincinnati, OH 45221.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0700607104/DC1.
To whom correspondence may be addressed. E-mail: george.stan{at}uc.edu, glorimer{at}umd.edu, thirum{at}glue.umd.edu, or brb{at}nih.gov
© 2007 by The National Academy of Sciences of the USA
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