| People
- Faculty
- Professor:
Joan-Emma Shea |
| Field(s): |
Theoretical/Biophysical Chemistry |
 |
| Email: |
shea@chem.ucsb.edu |
| Phone: |
(805)
893-
5604 |
Fax:
(805)
893-
4120 |
| Office: |
4130 Chem |
 |
Selected
Publications |
|
Go
to Research Group website |
| Bio: |
Dr. Shea received her B.Sc. in Chemistry from McGill University, Quebec in 1992 and her Ph.D. in physical chemistry from MIT in 1997. She pursued her postdoctoral studies at the Scripps Research Institute. After a year as an assistant professor of chemistry at the University of Chicago, Dr. Shea joined the faculty at UCSB in 2001. |
|
Current
Research
Research in the Shea group focuses on developing and applying the techniques of statistical and computational physics to the study of biological problems. Current work involves the investigation of cellular processes such as in-vivo protein folding and protein aggregation.
Protein Folding in the Cell
Proteins are among the most important building blocks of life. They originate in the ribosome where they are synthesized as a chain of amino acids. Their sequence is encoded in the cellular DNA, and this sequence in turn determines the fold of the protein. Only in its folded state can the protein serve its biological role. The kinetic and thermodynamic mechanisms that enable the protein to reach its three dimensional structure from a one dimensional chain of amino acids are still under debate, despite over thirty years of sustained theoretical and experimental effort.
Protein Intermediates, Protein Misfolding and Aggregation
Experiments have shown that proteins can fold efficiently through a large number of different mechanisms. Certain proteins appear to fold in a "two-state" manner, proceeding directly from the unfolded state to the folded state, while others adopt a multi-state mechanism, significantly populating one or more stable intermediate species as they fold. The reasons behind these mechanistic differences are not well understood. In fact, it is unclear why nature would have evolved a multi-state folding mechanism when proteins can fold without intermediates.
The role of intermediates in folding is hotly debated, with experimental studies reaching seemingly contradictory conclusions. Certain experiments suggest that intermediates aid folding by guiding the protein to the folded state while other studies imply that intermediates hinder folding by acting as kinetics traps. Our research focuses in part on establishing the mechanistic differences between two and multi-state folders and determining which factors (structural, thermodynamic and kinetic) are responsible for each type of behavior.
Additionally, the formation of certain types of intermediates in the cell can be problematic. The crowded cellular environment is conducive to the formation of "misfolded" intermediate protein species that can interact to form stable but biologically non-functional aggregated structures. Diseases such as Alzheimer's, cystic fibrosis and type II diabetes have been linked to such aggregation processes. Interestingly, the ability to form aggregated structures is not unique to disease related proteins. Recent studies have demonstrated that given suitable conditions, any protein is capable of aggregating. This implies that the aggregated state is an inherent structural form of a protein, just like the unfolded and the folded state.
We are investigating the conditions that lead to the formation of misfolded protein structures as well as the mechanism by which these structures associate to form aggregates. Our approach involves a combination of Monte Carlo and Molecular Dynamics simulations using coarse grained as well as atomically detailed models. These simulations are complemented by analytical studies.
|
| Selected
Research Publications |
| Self-assembly of beta-sheet forming peptides into chiral fibrillar clusters. G. Bellesia and J.-E. Shea J. Chem. Phys. (2007) in press. |
| Stability of a protein tethered to a surface, M. Friedel, A. Baumketner and J.-E. Shea J. Chem. Phys. 126, 095101 (2007). |
| The structure of the Alzheimer amyloid-beta(10-35) peptide probed through replica exchange molecular dynamics simulations in explicit solvent. Andrij Baumketner and Joan-Emma Shea J. Mol. Biol. (2007), vol 366 pages 275-285. |
| Folding on the Chaperone: Yield Enhancement Through Loose Binding,
A.I. Jewett and J.-E. Shea, Journal of Molecular Biology (2006), vol 363, pages 945-957. |
| M. Friedel, A. Baumketner and J.-E. Shea, Effects of surface tethering on protein folding mechanisms, Proc. Nat. Acad. Sci. USA, 2006 103: 8396-8401. |
| Andrij Baumketner, Summer L. Bernstein, Thomas Wyttenbach, Gal Bitan, David B. Teplow, Michael T. Bowers, and Joan-Emma Shea, Structure of the 21-30 fragment of amyloid-beta protein, Prot. Sci., 2006, 15: 1239-1247. |
|
|