How do molecular chaperones help proteins fold?
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.
Movie made by James Partridge
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 movie of the Hsp90 chaperone motions). 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.
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.
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.
Street TO, Zeng X, Pellarin R, Bonomi M, Sali A, Kelly MJ, Chu F, Agard DA. Agard Elucidating the mechanism of substrate recognition by the bacterial Hsp90 molecular chaperone. J. Mol. Biol. 2014.
Genest O, Reidy M, Street TO, Hoskins JR, Camberg JL, Agard DA, Masison DC, Wickner S. Uncovering a region of heat shock protein 90 important for client
binding in E. coli and chaperone function in yeast. Mol Cell. 2013.
Street TO, Lavery LA, Verba KA, Lee CT, Mayer MP, Agard DA. Cross-monomer
substrate contacts reposition the Hsp90 N-terminal domain and prime the chaperone activity. J Mol Biol. 2012.
Street TO, Lavery LA, Agard DA. Substrate binding drives large-scale
conformational changes in the Hsp90 molecular chaperone. Mol Cell. 2011.
Krukenberg KA, Street TO, Lavery LA, Agard DA. Conformational dynamics of the molecular chaperone Hsp90. Q Rev Biophys. 2011.
Street TO, Krukenberg KA, Rosgen J, Bolen DW, Agard DA. Osmolyte-induced
conformational changes in the Hsp90 molecular chaperone. Protein Sci. 2010.
Krukenberg KA, Southworth DR, Street TO, Agard DA. pH-dependent conformational changes in bacterial Hsp90 reveal a Grp94-like conformation at pH 6 that is highly active in suppression of citrate synthase aggregation. J Mol Biol. 2009.
Street TO, Barrick D. Predicting repeat protein folding kinetics from an
experimentally determined folding energy landscape. Protein Sci. 2009.
Perskie LL, Street TO, Rose GD. Structures, basins, and energies: a
deconstruction of the Protein Coil Library. Protein Sci. 2008.
Street TO, Courtemanche N, Barrick D. Protein folding and stability using
denaturants. Methods Cell Biol. 2008.
Street TO, Fitzkee NC, Perskie LL, Rose GD. Physical-chemical determinants of
turn conformations in globular proteins. Protein Sci. 2007.
Street TO, Bradley CM, Barrick D. Predicting coupling limits from an
experimentally determined energy landscape. Proc Natl Acad Sci U S A. 2007.
Street TO, Bolen DW, Rose GD. A molecular mechanism for osmolyte-induced
protein stability. Proc Natl Acad Sci U S A. 2006.
Street TO, Rose GD, Barrick D. The role of introns in repeat protein gene
formation. J Mol Biol. 2006.
Street TO, Bradley CM, Barrick D. An improved experimental system for
determining small folding entropy changes resulting from proline to alanine
substitutions. Protein Sci. 2005.
Fitzkee NC, Fleming PJ, Gong H, Panasik N Jr, Street TO, Rose GD. Are
proteins made from a limited parts list? Trends Biochem Sci. 2005.
Last review: July 29, 2014