3D Electron Microscopy Of Molecular Assemblies
Zhang Lab University of Pittsburgh School of Medicine Department of Structural Biology
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Structure and Function of the Receptor Signaling Complex in Bacterial Chemotaxis

Cells use signal transduction pathways to monitor their environment and implement appropriate responses to change. In some bacterial pathogens, directed motility in response to external chemicals (chemotaxis) is crucial for colonization and infection, and the signal transduction systems that mediate such responses are potential targets for antimicrobial drug development.

The chemotactic signaling pathway in E. coli cells respond to the changes in their chemical Description: pnas_chemotaxis environment through a signaling complex consisting of transmembrane chemotaxis receptors, the histidine autokinace CheA and the coupling protein CheW. Moreover, a few thousand receptor signaling complexes form higher order assemblies at the cell pole and these are responsible for the extraordinary gain in chemotaxis signaling. Despite the determination of high resolution structures of the individual soluble domains of the receptor, CheA, and CheW, the structure of the receptor-CheA-CheW ternary complex and the architecture of the extended higher order assembly have remained elusive. The larger size and dynamic nature make the signaling complex a difficult target for any structural study. We are using a ovel combination of cyro-electron tomography (cyroET) of native in vivo clusters and 2D electron crystallography of in vitro reconstituted complexes, aided by site-directed mutagenesis and molecular modeling, to determine the molecular interactions, and hence the precise mechanisms of receptor-mediated cooperative signaling. Our unique strategy offers a comprehensive understanding of receptor-kinase interactions and signaling processing.

Cassidy C. K, Himes B. A., Alvarez F. J., Ma J., Zhao G., Perilla J. R., Schulten K. and Zhang P.* (2015) CryoEM and Computer Simulations Reveal a Novel Kinase Conformational Switch in Bacterial Chemotaxis Signaling. Elife. 2015 Nov 19;4. pii: e08419. doi: 10.7554/eLife.08419.

Khursigara C.M.*, Wu X. *, Zhang P. *, Lefman J. and Subramaniam S. (2008) Role of HAMP domains in chemotaxis signaling by bacterial chemoreceptors. Proc Natl Acad Sci USA 105(43):16555-60.

Zhang P., Khursigara C.M., Hartnell L.M., Subramaniam S. (2007) Direct visualization of E.coli chemotaxis receptor arrays using cryo-electron microscopy. Proc Natl Acad Sci USA 104(10):3777-81

Zhang P., Weis R. M., Peters P. J., Subramaniam S. (2007) Electron tomography of bacterial chemotaxis receptor assemblie. Methods Cell Biol. 79:373-84.

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