Location

Rochester

Contact

toft.david@mayo.edu

Summary

Our laboratory is interested in the characterization of cytoplasmic molecular chaperones; proteins that assist in the folding, processing or degradation of proteins in the cytoplasm. These proteins are essential to living cells, but their mechanisms of action are not well understood. We have developed cell-free systems for studying the functions of the two major chaperones, hsp70 and hsp90, and several of their co-chaperones. hsp90 is the main focus of our laboratory. Its chaperoning activity is essential for proper functioning of many cell regulatory proteins such as steroid receptors, many protein kinases, telomerase and NOS.

The progesterone receptor is a nuclear transcription regulator that, when inactive, is sequestered in complexes involving hsp70 and hsp90. These complexes keep the receptor inactive, but also promote proper folding to a state capable of responding to progesterone. At least five additional co-chaperones are needed to form these complexes through an ordered ATP-dependent process. This system allows us to test the importance or function of each protein component in the assembly processes. Protein binding studies plus in vitro mutagenesis are being used to identify sites of protein:protein interaction and to describe conformational transitions in hsp70 and hsp90 that are directed, in part, by the binding of ATP or ADP.

We are performing a variety of studies to describe functional domains of hsp90 and its sites for interaction with co-chaperones and with protein substrates. In addition, we are studying the mode of action of geldanamycin, a drug that inhibits several functions of hsp90. It binds to hsp90 and blocks the ATP-dependent conformational changes that are required for hsp90 activities. Geldanamycin limits a variety of cell signaling pathways and cell growth and it is a potential drug for cancer chemotherapy.

Recent Publications

See my publications

Professional Details

Primary Appointment

  1. Biochemistry

Academic Rank

  1. Professor of Biochem/Molecular Biology

Education

  1. Post-doctoral Fellowship - Dr. G.C. Mueller University of Wisconsin, Madison
  2. Predoctoral Fellowship - Dr. Jack Gorski University of Illinois
  3. PhD - Cell Biology University of Illinois
  4. MA - Physiology University of Illinois
  5. BA - Biology Gustavus Adolphus College
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BIO-00077092

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