Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Ion Channels: From Structure Refinement and Remodeling to Functional Mechanisms
Ion channels and other membrane proteins, relative to water-soluble proteins, have less intrinsic stability and are more prone to influences of the solubilizing environments. Indeed, our recent assessment of membrane protein structures in the Protein Data Bank identified many cases of potential distortions in transmembrane domains, attributable to sample preparations used for X-ray crystallography and solution NMR spectroscopy (Zhou & Cross, 2013). To achieve native-like structures, we use solid-state NMR data for refinement through restrained molecular dynamics simulations in native-like environments, i.e., in lipid bilayers. For the Influenza M2 protein (an acid-activated proton-selective channel), our study further focused on its functional center, i.e., a histidine tetrad within the channel pore that acts as both the pH sensor and ion selectivity filter. Based on solid-state NMR data and quantum chemistry calculations, we developed a mechanism for acid activation and proton conductance (Sharma et al., 2010). A theoretical model built on this mechanism was able to quantitatively rationalize the M2-mediated current's solvent isotope effect and dependences on pH and transmembrane voltage (Zhou, 2011). In other studies, we have begun to remodel transmembrane domains from crystal structures, both for correcting distortions (Heymann et al., 2013) and for generating structural models in different functional states (Dai & Zhou, 2014); and to design electrophysiological studies for validating functional mechanisms (Kazi et al., 2014).
M. Sharma, M. Yi, H. Dong, H. Qin, E. Peterson, D. D. Busath, H.-X. Zhou, and T. A. Cross (2010). Insight into the mechanism of the Influenza A proton channel from a structure in a lipid bilayer. Science 330, 509-512.
H.-X. Zhou (2011). A theory for the proton transport of the influenza virus M2 protein: extensive test against conductance data. Biophys. J. 100, 912-921.
G. Heymann, J. Dai, M. Li, S. D. Silberberg, H.-X. Zhou, and K. J. Swartz (2013). Inter- and intrasubunit interactions between transmembrane helices in the open state of P2X receptor channels. Proc. Natl. Acad. Sci. USA 110, E4045-E4054.
J. Dai and H.-X. Zhou (2014). General rules for the arrangements and gating motions of pore-lining helices in homomeric ion channels. Nat. Commun. 5, 4641. R. Kazi, J. Dai, C. Sweeney, H.-X. Zhou, and L. P. Wollmuth (2014). Mechanical coupling maintains the fidelity of NMDA receptor-mediated currents. Nat. Neurosci. 17, 914-922.
Department of Physics and Institute of Molecular Biophysics