Abstract

All chaperonins mediate ATP-dependent polypeptide folding by confining substrates within a central chamber. Intriguingly, the eukaryotic chaperonin TRiC (also called CCT) uses a built-in lid to close the chamber, whereas prokaryotic chaperonins use a detachable lid. Here we determine the mechanism of lid closure in TRiC using single-particle cryo-EM and comparative protein modeling. Comparison of TRiC in its open, nucleotide-free, and closed, nucleotide-induced states reveals that the interdomain motions leading to lid closure in TRiC are radically different from those of prokaryotic chaperonins, despite their overall structural similarity. We propose that domain movements in TRiC are coordinated through unique interdomain contacts within each subunit and, further, these contacts are absent in prokaryotic chaperonins. Our findings show how different mechanical switches can evolve from a common structural framework through modification of allosteric networks.

1. Graduate Program in Structural and Computational Biology and Molecular Biophysics, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030, USA.
2. National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030, USA.
3. Department of Biological Sciences and BioX Program, Clark Center E200A, Stanford University, Stanford, California 94305-5020, USA.
4. Departments of Biopharmaceutical Sciences and Pharmaceutical Chemistry and California Institute for Quantitative Biomedical Research, University of California at San Francisco, 1700 4th Street, San Francisco, California 94158-2330, USA.
5. Present addresses: Gatan Inc., Pleasanton, California 94588, USA (C.R.B.), Massachusetts Institute of Technology, Department of Biology, Cambridge, Massachusetts 02139, USA (A.S.M.) and School of Crystallography, Birkbeck College, University of London, London WC1E 7HX, UK (M.T.).

Correspondence to: Judith Frydman³ e-mail: jfrydman@leland.stanford.edu

Correspondence to: Wah Chiu^1,2 e-mail: wah@bcm.edu

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