Research Description

HEAT-SHOCK PROTEINS AND GENES

Summary: My laboratory investigates the heat-shock protein Hsp70, its encoding genes, and its regulation in Drosophila as a model system for understanding evolutionary adaptation. Hsp70 is a molecular chaperone that deters stress-induced protein aggregation, but has numerous other functions. Hsp70 is necessary for full-strength tolerance (in terms of survival, normal development, normal function) of high temperature. Such tolerance is critical in nature, where non-adult Drosophila undergo harmful to lethal high temperatures. In nature, Drosophila populations vary in stress tolerance and Hsp70 levels. Our current major focus is on understanding the genomic basis for this variation. The number of hsp70 gene copies and evolution of the hsp70 coding sequence are partial or inadequate explanations. Evidently cis-regulatory regions such as proximal promoters underlie intraspecific variation in Hsp70 levels. Repeated insertion of mobile genetic elements into these promoters is a recurrent mechanism of evolution.

What are heat-shock proteins?

Why are heat-shock proteins important?

Are heat-shock proteins important in nature?

How is natural variation in Hsp70 expression encoded at the genomic level?

Current projects

What are heat-shock proteins?

Many heat-shock proteins, including those that my lab studies, are "molecular chaperones", proteins that play roles in the folding, transport, synthesis, and quality control of other proteins. One especially important role of molecular chaperones, particularly in the context of extreme temperatures and other stresses, is in coping with the impact of such stresses on proteins: under stress, proteins may lose their native conformation and expose regions that cause normally separate proteins to aggregate. Molecular chaperones can recognize and bind such proteins, deterring their aggregation.

The cartoon above, adapted from the work of Bernd Bukau and many others, illustrates the function of DnaK-Hsp70 superfamily proteins. An N-terminal domain binds nucleotide, ATP or ADP. A C-terminal domain includes a peptide-binding domain (pink) and a helical lid. These domains interact. When the nucleotide-binding domain binds ATP, unfolded protein interacts weakly and transiently with the peptide-binding domain. When the N-terminal domain hydrolyzes the ATP, the resultant ADP induces a conformational change resulting in increased affinity of the peptide-binding domain for unfolded protein and movement of the helical lid. These actions collectively trap the unfolded protein; while trapped, its probability of incorporation into aggregates is reduced. Replacement of the ADP with ATP then causes the chaperone to revert to its weakly-binding state.

Much of my research investigates Hsp70, the most abundant inducible heat-shock protein in Drosophila and a member of the DnaK-Hsp70 superfamily of chaperones. Members of this superfamily are present in all living things except the most primitive archaebacteria. Importantly, these proteins have functions other than chaperoning, including interactions with apoptosis, signaling pathways, transcription factors, cell cycle, intracellular calcium, and membrane conductance.

For a complete list of laboratory publications on the above topics, go to

LIST OF PUBLICATIONS