title: Gating mechanism of the influenza A M2 channel revealed by 1D and 2D IR spectroscopies.
abstract: The pH-controlled M2 protein from influenza A is a critical component of the virus and serves as a target for the aminoadamantane antiflu agents that block its H+ channel activity. To better understand its H+ gating mechanism, we investigated M2 in lipid bilayers with a new combination of IR spectroscopies and theory. Linear Fourier transform infrared (FTIR) spectroscopy was used to measure the precise orientation of the backbone carbonyl groups, and 2D infrared (IR) spectroscopy was used to identify channel-lining residues. At low pH (open state), our results match previously published solid-state NMR and X-ray structures remarkably well. However, at neutral pH when the channel is closed, our measurements indicate that a large conformational change occurs that is consistent with the transmembrane alpha-helices rotating by one amino acid register--a structural rearrangement not previously observed. The combination of simulations and isotope-labeled FTIR and 2D IR spectroscopies provides a noninvasive means of interrogating the structures of membrane proteins in general and ion channels in particular.
authors.affiliation: The Alexander Silberman Institute of Life Sciences, Department of Biological Chemistry, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Joshua
authors.initials: J
authors.lastname: Manor
authors.forename: Prabuddha
authors.initials: P
authors.lastname: Mukherjee
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Lin
authors.forename: Hadas
authors.initials: H
authors.lastname: Leonov
authors.forename: James L
authors.initials: JL
authors.lastname: Skinner
authors.forename: Martin T
authors.initials: MT
authors.lastname: Zanni
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D019295:Computational Biology; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000502:physiology; D008954:Models, Biological; D008958:Models, Molecular; D011487:Protein Conformation; D011522:Protons; D012399:Rotation; D013055:Spectrophotometry, Infrared / Q000379:methods; D014763:Viral Matrix Proteins / Q000737:chemistry* / Q000378:metabolism*; D000086082:Viroporin Proteins
chemical_list: D011522:Protons; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins