Department of Biochemistry

Timothy Street

Timothy Street faculty imageAssociate Professor of Biochemistry

Research Description

Mechanisms of protein folding in the cell

The balance of protein folding and degradation is one of the most fundamental activities of the cell, and is a critical point of intervention in cancer, metabolic, and aging diseases. Molecular chaperones are the central players that regulate the cell's repertoire of folded proteins, and as a consequence chaperones influence virtually every cellular process under both healthy and disease conditions. Despite their central influence, the functional mechanisms of many chaperones are poorly understood. Work in my lab is focused on revealing these mechanisms.

Dissecting a chaperone mechanism requires working at the interface of structural biology and protein folding. From a structural view, chaperones represent a fascinating class of molecular machines that undergo dramatic structural changes, often by utilizing ATP chemical energy (for example, see conformational changes of the Hsp90 chaperone in adjacent figure). These motions are then coupled to changes in the folding of their substrate proteins. However, it is not known how chaperones identify their binding partners in the complex cellular environment, and it is not known how chaperones affect protein folding.

conformational changes of the Hsp90 chaperone

These fundamental questions will be answered by combining structural tools (x-ray crystallography, NMR, FRET, small angle x-ray scattering) with the tools of protein folding (thermodynamics, kinetics, energy landscape concepts) and computational modeling. In addition to these established techniques, new assays are critically needed to test chaperone mechanisms in live cells. One possibility is to design in-vivo protein-folding biosensors, which could have far-reaching practical applications.

Combination of structural tools (x-ray crystallography, NMR, FRET, small angle x-ray scattering) with the tools of protein folding (thermodynamics, kinetics, energy landscape concepts) and computational modeling

Some therapeutic proteins are challenging to produce on a large scale because they require chaperones for optimal folding. There is a strong economic incentive to optimize the folding efficiency of these proteins. As a result, there is an exciting potential to use the mechanistic principles underlying chaperone function to rationally design new therapeutic proteins that fold more efficiently.

Selected Publications