This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Molecular chaperones are key mediators of cellular folding. The eukaryotic chaperonin TRiC/CCT is essential to fold a wide array of cellular proteins. Its substrates include key proteins essential for cell division, such as actin, tubulin, cyclin E and the tumor suppressor protein VHL.TRiC is a 1 MDa ring-shaped hetero-oligomeric complex that uses ATP-binding and hydrolysis to drive the folding cycle. Little is known about the conformational changes that accompany ATP-binding and hydrolysis. We have recently carried out biochemical and biophysical studies to characterize its conformational cycle. The structural analysis by cryoEM will provide a critical complement to our biochemical analysis.Biomedical relevance of the study: Recent findings indicating that misfolding and accumulation of incorrectly folded proteins is the molecular basis of many diseases, including cancer, Alzheimer's and Prion Diseases, underscoring the importance of understanding the mechanisms of chaperone-mediated folding. Thus, knowledge of how chaperones function to promote folding in the cell should eventually provide the basis for controlling protein function under normal conditions, and during abnormal conditions of environmental stress and disease. Research goals and its relationship to ongoing research: TRiC is a ATP-dependent chaperonin with a built-in lid. Our preliminary results using biochemical methods and Small Angle X-ray Scattering indicate changes in ATP during the hydrolysis cycle drive the closing and opening of the lid. The collaboration with NCMI will shed light on the conformation adopted by TRiC during the ATP hydrolysis cycle. Using analogues of ATP that mimic distinct stages of the ATP hydrolysis reaction we will detect the conformational changes that drive chaperonin-mediated folding. In a separate suite of studies, we will also investigate the structure of the TRiC-bound substrate. These studies will be an ideal complement to our mechanistic biochemical and biophysical studies.In addition, we will also study the archael homolog chaperonin called Mm-cpn. This machine is also a 16-mer, but with only one kind of polypeptide chain.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-BPC-K (40))
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Baylor College of Medicine
Schools of Medicine
United States
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