In this project, a small and specialized volume of cytoplasm associated with a cluster of chemotactic receptors on the surface of the bacterium Escherichia coli will be analyzed in great detail, using computer modeling, stochastic simulation techniques, and a novel 3D prototyping technique. Models of the receptors and associated proteins, at atomic resolution, will be assembled into a two-dimensional lattice resembling the cluster of receptors in the bacterial membrane in an arrangement consistent with biochemical, kinetic, mutational and behavioral data. The cytoplasmic domains of the receptors will then be used to define a small volume of cytoplasm subjacent to the plasma membrane and to examine the concentrations, distributions and diffusive behavior of """"""""soluble"""""""" enzymes that interact with the receptors in the course of adaptation. The feasibility of a two-handed, """"""""brachiation"""""""" motion of enzymes through the lattice, due to their possession of two relatively weak binding sites for the receptors will be examined. We will also explore the theoretical possibility that conformational changes might spread, from one receptor to its neighbors in the lattice via intervening proteins, and thereby lead to the emergence of large-scale coherent patterns of activity. The results of this study are likely to provide novel insight not only on bacterial chemotaxis but also, more generally, on other membrane-associated protein complexes, such as focal adhesions in fibroblasts and postsynaptic densities in the vertebrate central nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064713-02
Application #
6620291
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Deatherage, James F
Project Start
2002-06-01
Project End
2005-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$162,000
Indirect Cost
Name
University of Cambridge
Department
Type
DUNS #
226552610
City
Cambridge
State
Country
United Kingdom
Zip Code
CB2 1-TN
Zonia, Laura; Bray, Dennis (2009) Swimming patterns and dynamics of simulated Escherichia coli bacteria. J R Soc Interface 6:1035-46
DePristo, Mark A; Chang, Lynne; Vale, Ronald D et al. (2009) Introducing simulated cellular architecture to the quantitative analysis of fluorescent microscopy. Prog Biophys Mol Biol 100:25-32
Silversmith, Ruth E; Levin, Matthew D; Schilling, Elmar et al. (2008) Kinetic characterization of catalysis by the chemotaxis phosphatase CheZ. Modulation of activity by the phosphorylated CheY substrate. J Biol Chem 283:756-65
Bray, Dennis; Levin, Matthew D; Lipkow, Karen (2007) The chemotactic behavior of computer-based surrogate bacteria. Curr Biol 17:12-9
Lipkow, Karen (2006) Changing cellular location of CheZ predicted by molecular simulations. PLoS Comput Biol 2:e39
Grati, M'hamed; Schneider, Mark E; Lipkow, Karen et al. (2006) Rapid turnover of stereocilia membrane proteins: evidence from the trafficking and mobility of plasma membrane Ca(2+)-ATPase 2. J Neurosci 26:6386-95
Andrews, Steven S (2005) Serial rebinding of ligands to clustered receptors as exemplified by bacterial chemotaxis. Phys Biol 2:111-22
Lipkow, Karen; Andrews, Steven S; Bray, Dennis (2005) Simulated diffusion of phosphorylated CheY through the cytoplasm of Escherichia coli. J Bacteriol 187:45-53
Goldman, Jacki; Andrews, Steven; Bray, Dennis (2004) Size and composition of membrane protein clusters predicted by Monte Carlo analysis. Eur Biophys J 33:506-12
Bray, Dennis; Duke, Thomas (2004) Conformational spread: the propagation of allosteric states in large multiprotein complexes. Annu Rev Biophys Biomol Struct 33:53-73

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