Research

Heat shock protein 90 (Hsp90), a ubiquitous chaperone comprising 1-2% of cytosolic proteins, is essential for cell viability in eukaryotes. Hsp90 plays a critical role in cellular processes ranging from signal transduction to cellular division. Unlike other chaperones, such as GroEL, Hsp90 does not fold linear polypeptides; rather (with the aid of co-chaperones) the chaperone is believed to induce subtle conformational re-arrangements in near native proteins making Hsp90 unique in function. Despite its obvious importance very little is known about the molecular mechanism of Hsp90.

Like many other chaperones, nucleotide binding and hydrolysis drives the protein through its chaperone cycle in which three major conformations have been identified. Recent SAXS and EM experiments reveal that the inferred set of apo solution conformations differs from the crystal structure and that nucleotide biases but does not uniquely determine Hsp90’s conformational state. These observations demonstrate the relevance of conformational dynamics and call into question the prevalent deterministic mechanism for Hsp90 function.

To investigate the mechanism of Hsp90 in greater molecular detail, I am currently focused on connecting conformational state(s) and dynamics of Hsp90 (obtained by single-molecule techniques) to bulk enzymatic kinetics in order to assign the geometrical state(s) of the chaperone to its progress through ATP hydrolysis.  

Publications

A. Levskaya, A. Chevalier, J. Tabor, Z. Simpson, L. Lavery, M. Levy, E. Davidson, A. Scouras, A. Ellington, E. Marcotte, and C. Voigt.  “Engineering Escherichia coli to see light”.  Nature 438, (7067), 441-442. 

T. Chu, F. Shieh, L. Lavery, M. Levy, R. Richards-Kortum, B. Korgel, A. Ellington.  “Labeling Tumor Cells with Fluorescent Nanocrystal-Aptamer Bioconjugates”.  Biosensors and Bioelectronics 21, (10), 1859-1866.

T. Chu, J. Marks III, L. Lavery, S. Faulkner, M. Rosenblum, A. Ellington, M. Levy.  “Aptamer: toxin conjugates that specifically target prostate tumor cells”, Cancer Research 66, (12), 5989-5992.