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9th International Conference on Structural Biology

Zurich, Switzerland

Timothy A. Cross

Timothy A. Cross

Florida State Univ. & National High Magnetic Field Lab, USA

Title: Membrane Protein Structure, Dynamics & Function: Oriented Sample and Magic Angle Sample Spinning Solid State NMR

Biography

Biography: Timothy A. Cross

Abstract

Statement of the Problem: Unlike water soluble proteins that have a relatively homogeneous environment, membrane proteins exist in a dramatically heterogeneous environment. The result is protein structure that is stabilized by a different balance of molecular interactions for the membrane embedded portion of the protein compared to the water soluble or membrane interfacial regions of the protein. The result is a need to model the membrane environment as closely as possible to that of the native environment for structural, dynamic and functional characterizations. Methodology: Biological solid state NMR provides a unique opportunity to model the membrane environment with liquid crystalline lipid bilayers and a wide variety of lipids. The samples can be prepared either as liposomes for magic angle sample spinning (MAS) or as uniformly oriented samples (OS) for the spectroscopy. The former provides solution like spectra for both distance and isotropic chemical shift restraints, while oriented samples provide absolute restraints that restrain the atomic sites in the protein structure to the bilayer normal. In addition to structural restraints it is possible to characterize the protein’s dynamics and kinetic rates. Findings, Conclusion & Significance: The structure, dynamics and kinetics associated with the M2 proton channel from influenza A have been characterized yielding a unique mechanism for proton transport by this important drug target. In addition, the cholesterol binding to M2 has been found to stabilize the amphipathic helix in the lipid interface an essential feature for this protein’s functional role in viral budding. Recent structural studies of the CrgA protein from Mycobacterium tuberculosis  have characterized a dimeric structure stabilized primarily by intermolecular b-sheet in the membrane interfacial region. The protein is part of the cell division apparatus and appears to play a role in recruiting multiple proteins to the divisome, potentially through its transmembrane domain.

References:

1. Zhou, H.-X. & Cross, T.A. (2013) “Influences of Membrane Mimetic Environments on Membrane Protein Structures” Annual Reviews of Biophysics 42:361-392.

2. Sharma, M., Yi, M., Dong, H., Qin, H., Petersen, E., Busath, D.D., Zhou, H.-X. & Cross, T.A. (2010)  “Insight into the Mechanism of the Influenza A Proton Channel from a Structure in a Lipid Bilayer” Science 330:509-512.

3. Murray, D., Das, N., Cross, T.A. (2013) “Solid State NMR Strategy for Characterizing Native Membrane Protein Structures” Accounts of Chemical Research 46:2172-2181.

4. Miao, Y., Fu, R., Zhou, H.-X. & Cross, T.A. (2015) Dynamic, Short Hydrogen Bonds in Histidine Tetrad of Full-Length M2 H+ Channel Reveals Tetrameric Structural Heterogeneity and Functional Mechanism” Structure 23:2300-2308.

5. Das, N., Dai, J., Hung, I., Rajagopalan, M., Zhou, H.-X. & Cross, T.A. (2015) “Structure of CrgA, a Cell Division Structural and Regulatory Protein from Mycobacterium tuberculosis in Lipid Bilayers” Proc. Natl. Acad. Sci. 112:E119-E126.