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Media type:
E-Article
Title:
Folding trajectories of human dihydrofolate reductase inside the GroEL–GroES chaperonin cavity and free in solution
Contributor:
Horst, Reto;
Fenton, Wayne A.;
Englander, S. Walter;
Wüthrich, Kurt;
Horwich, Arthur L.
imprint:
Proceedings of the National Academy of Sciences, 2007
Published in:Proceedings of the National Academy of Sciences
Language:
English
DOI:
10.1073/pnas.0710042105
ISSN:
1091-6490;
0027-8424
Origination:
Footnote:
Description:
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The chaperonin GroEL binds non-native polypeptides in an open ring via hydrophobic contacts and then, after ATP and GroES binding to the same ring as polypeptide, mediates productive folding in the now hydrophilic, encapsulated
<jats:italic>cis</jats:italic>
chamber. The nature of the folding reaction in the c
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cavity remains poorly understood. In particular, it is unclear whether polypeptides take the same route to the native state in this cavity as they do when folding spontaneously free in solution. Here, we have addressed this question by using NMR measurements of the time course of acquisition of amide proton exchange protection of human dihydrofolate reductase (DHFR) during folding in the presence of methotrexate and ATP either free in solution or inside the stable cavity formed between a single ring variant of GroEL, SR1, and GroES. Recovery of DHFR refolded by the SR1/GroES-mediated reaction is 2-fold higher than in the spontaneous reaction. Nevertheless, DHFR folding was found to proceed by the same trajectories inside the
<jats:italic>cis</jats:italic>
folding chamber and free in solution. These observations are consistent with the description of the chaperonin chamber as an “Anfinsen cage” where polypeptide folding is determined solely by the amino acid sequence, as it is in solution. However, if misfolding occurs in the confinement of the chaperonin cavity, the polypeptide chain cannot undergo aggregation but rather finds its way back to a productive pathway in a manner that cannot be accomplished in solution, resulting in the observed high overall recovery.
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