Os chaperones instigam o dobramento exato de proteínas, mas como?

segunda-feira, janeiro 25, 2010

Chaperonins Prompt Proper Protein Folding -- But How?

ScienceDaily (Jan. 25, 2010) — In proper society of yesterday, a chaperone ensured that couples maintained appropriate courting rituals. In biology, a group of proteins called chaperonins make sure that proteins are folded properly to carry out their assigned roles in the cells.

In a new study in archaea (single-celled organisms without nuclei to enclose their genetic information), a consortium of researchers from Baylor College of Medicine and Stanford University in California discovered how the Group II chaperonins close and open folding chambers to initate the folding event and to release the functional protein to the cell. A report of their work appears in the current issue of the journal Nature.

Archaea is one of three major divisions in the classification of living organisms. The other two are bacteria and eukaryotes. Archaea lack a nucleus but have other characteristics that are similar to those of eukaryotes, which include human beings.

"The important thing about the chaperonin molecule is that it is key to folding proteins in the cell -- proteins such as actin, tubulin and tumor suppressors," said Dr. Wah Chiu, professor of biochemistry and molecular biology at BCM and a senior author of the report.

"Previously, people had studied chaperonins in the bacteriaEscherichia coli," said Chiu, also director of the National Center for Macromolecular Imaging and of the Nanomedicine Development Center at BCM. "We wanted to look at how chaperonins operated in a new class of organisms, and we chose the archaea."

It turned out that the archaea have a different type of chaperonin dubbed Group II. The structure of this kind of chaperonin is more similar to that of mammals. In essence, both types of chaperonin act as molecular machines, assisting proper protein within the cell. To the surprise of Chiu and his colleagues, the Group II chaperonin worked differently from Group I chaperonins previously studied in E. coli.

Nature 463, 379-383 (21 January 2010) | doi:10.1038/nature08701; Received 24 June 2009; Accepted 16 November 2009Mechanism of folding chamber closure in a group II chaperonin

Junjie Zhang1,2, Matthew L. Baker2, Gunnar F. Schröder3,5, Nicholai R. Douglas4, Stefanie Reissmann4,5, Joanita Jakana2, Matthew Dougherty2, Caroline J. Fu2, Michael Levitt3, Steven J. Ludtke1,2, Judith Frydman4 & Wah Chiu1,2

Graduate Program in Structural and Computational Biology and Molecular Biophysics,
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
Department of Structural Biology,
Department of Biology and BioX Program, Stanford University, Stanford, California 94305, USA
Present addresses: Institut für Strukturbiologie und Biophysik (ISB-3), Forschungszentrum Jülich, 52425 Jülich, Germany (G.F.S.); Max-Planck-Institut für terrestrische Mikrobiologie, Karl-von-Frisch Strasse, 35043 Marburg, Germany (S.R.).

Correspondence to: Judith Frydman4Wah Chiu1,2 Correspondence and requests for materials should be addressed to W.C. (Email: wah@bcm.edu) or J.F. (Email: jfrydman@stanford.edu).


Group II chaperonins are essential mediators of cellular protein folding in eukaryotes and archaea. These oligomeric protein machines, ~1 megadalton, consist of two back-to-back rings encompassing a central cavity that accommodates polypeptide substrates1, 2, 3. Chaperonin-mediated protein folding is critically dependent on the closure of a built-in lid4, 5, which is triggered by ATP hydrolysis6. The structural rearrangements and molecular events leading to lid closure are still unknown. Here we report four single particle cryo-electron microscopy (cryo-EM) structures of Mm-cpn, an archaeal group II chaperonin5, 7, in the nucleotide-free (open) and nucleotide-induced (closed) states. The 4.3 Å resolution of the closed conformation allowed building of the first ever atomic model directly from the single particle cryo-EM density map, in which we were able to visualize the nucleotide and more than 70% of the side chains. The model of the open conformation was obtained by using the deformable elastic network modelling with the 8 Å resolution open-state cryo-EM density restraints. Together, the open and closed structures show how local conformational changes triggered by ATP hydrolysis lead to an alteration of intersubunit contacts within and across the rings, ultimately causing a rocking motion that closes the ring. Our analyses show that there is an intricate and unforeseen set of interactions controlling allosteric communication and inter-ring signalling, driving the conformational cycle of group II chaperonins. Beyond this, we anticipate that our methodology of combining single particle cryo-EM and computational modelling will become a powerful tool in the determination of atomic details involved in the dynamic processes of macromolecular machines in solution.


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