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Folding of large multidomain proteins by partial encapsulation in the chaperonin TRiC/CCT

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons81102

Rüßmann,  Florian
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78751

Stemp,  Markus Johann
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons81104

Mönkemeyer,  Leonie
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77944

Etchells,  Stephanie A.
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons77798

Bracher,  Andreas
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78072

Hartl,  Franz-Ulrich
Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society;

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Citation

Rüßmann, F., Stemp, M. J., Mönkemeyer, L., Etchells, S. A., Bracher, A., & Hartl, F.-U. (2012). Folding of large multidomain proteins by partial encapsulation in the chaperonin TRiC/CCT. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109(52), 21208-21215. doi:10.1073/pnas.1218836109.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000E-B252-E
Abstract
The eukaryotic chaperonin, TRiC/CCT (TRiC, TCP-1 ring complex; CCT, chaperonin containing TCP-1), uses a built-in lid to mediate protein folding in an enclosed central cavity. Recent structural data suggest an effective size limit for the TRiC folding chamber of similar to 70 kDa, but numerous chaperonin substrates are substantially larger. Using artificial fusion constructs with actin, an obligate chaperonin substrate, we show that TRiC can mediate folding of large proteins by segmental or domain-wise encapsulation. Single or multiple protein domains up to similar to 70 kDa are stably enclosed by stabilizing the ATP-hydrolysis transition state of TRiC. Additional domains, connected by flexible linkers that pass through the central opening of the folding chamber, are excluded and remain accessible to externally added protease. Experiments with the physiological TRiC substrate hSnu114, a 109-kDa multidomain protein, suggest that TRiC has the ability to recognize domain boundaries in partially folded intermediates. In the case of hSnu114, this allows the selective encapsulation of the C-terminal similar to 45-kDa domain and segments thereof, presumably reflecting a stepwise folding mechanism. The capacity of the eukaryotic chaperonin to overcome the size limitation of the folding chamber may have facilitated the explosive expansion of the multidomain proteome in eukaryotes.