Targeting Chaperones

Chaperone Machinery Modulators in Cancer, Cardiovascular Disease and Neurodegeneration
Striatal monoaminergic terminals in Lewy body and Alzheimer's dementias
Striatal monoaminergic terminals in Lewy body and Alzheimer's dementias

We study protein quality control across translational models of cancer, cardiovascular disease and neurodegeneration with the goal of defining mechanisms of protein homeostasis and identifying therapeutic targets.

Our unified approach is based on the realization that a single cellular machinery, the Hsp90/Hsp70 based chaperone machinery, controls the activity, turnover and trafficking of hundreds of client proteins, and as such plays a critical role in the pathogenesis of these varied disorders.

In contrast to the classic model of individual chaperones interacting with unfolded proteins to facilitate their refolding, we will test a model in which the chaperone machinery functions in protein triage by interacting with client proteins in their near-native conformations to open and stabilize protein folding/ligand binding clefts.

Although chaperone machinery function has been studied intensively, a major limitation in the field is that the mechanism by which it triages unfolded or damaged proteins for degradation is poorly understood.

Our goal is to define this mechanism in order to develop strategies to achieve therapeutic benefits in disease.

Investigators Involved with this Hub:

Hub Publications:

Ahsan A, Ray D, Ramanand SG, Hegde A, Whitehead C, Rehemtulla A, Morishima Y, Pratt WB, Osawa Y, Lawrence TS, Nyati MK. Destabilization of the epidermal growth factor receptor
(EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. J Biol Chem. 2013;288:26879-86.
Ahsan A, Ramanand SG, Bergin IL, Zhao L, Whitehead C, Rehemtulla A, Ray D, Pratt WB, Lawrence TS, Nyati MK. Efficacy of an Epidermal Growth Factor Receptor (EGFR) Specific Peptide
Against EGFR-Dependent Cancer Cell lines and Tumor Xenografts. Neoplasia. 2014 (in press)
Pratt WB, Gestwicki JE, Osawa Y, Lieberman AP.  Targeting Hsp90/Hsp70-directed protein quality control for treatment of adult onset neurodegenerative diseases.  Ann Rev Pharmacol Toxicol, in press.
Yokom AL, Morishima Y, Lau M, Su M, Glukhova A, Osawa Y, Southworth DR.  Architecture of the nitric oxide synthase holoenzyme reveals large conformational changes and a calmodulin-driven release of the FMN domain.  J. Biol. Chem., in press.


NIH, GM077430, Chaperone recognition of xenobiotic-altered NO Synthase P450, Yoichi Osawa and Dan Southworth.
2014 Taubman Scholar Award, Sharlene Day
Children's Cardiomyopathy Foundation, Sharlene Day