Research Interests

My group has been studying molecular machines known as chaperonins, which provide kinetic assistance to protein folding in the cell. We originally identified this role when a genetic screen in baker's yeast turned up a mutant unable to fold newly-imported mitochondrial proteins to their native forms. An essential gene was affected, encoding heat shock protein 60, the subunit of a homo-tetradecameric 840 kDa double ring assembly. A closely related assembly present in the bacterial cytoplasm (GroEL), and a second less related class, in archaebacteria (thermosome) and in the eukaryotic cytosol (CCT), were observed to carry out similar actions, all requiring ATP. Structure and mechanism studies carried out with GroEL and its cooperating single ring, lid-like component, GroES, indicate that GroEL first binds non-native proteins in the central cavity of an open ring through hydrophobic contacts formed between such surfaces specifically exposed in non-native proteins and hydrophobic surfaces lining the chaperonin cavity. Polypeptide is then released into an encapsulated and now hydrophilic chamber formed by the binding of ATP and the cochaperonin GroES to the same ring as polypeptide. Folding in this privileged environment ends with ATP hydrolysis, which releases the ligands. Polypeptide molecules that have failed to reach native form become rapidly rebound to an open GroEL ring. Cycles of binding and ATP/GroES-driven folding thus ensure efficiency of this final step in the transfer of information from DNA to active protein.

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Primary Section

Section 21: Biochemistry

Secondary Section

Section 29: Biophysics and Computational Biology