Gating mechanism of the Influenza A M2 channel revealed by 1 and 2D-IR spectroscopies

• Published in: Structure (London) Vol. 17; no. 2; pp. 247 - 254
• Main Authors: Manor, Joshua, Mukherjee, Prabuddha, Lin, Yu-Shan, Leonov, Hadas, Skinner, J. L., Zanni, Martin T., Arkin, Isaiah T.
• Format: Journal Article
• Language: English
• Published: 13.02.2009
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2008.12.015

The pH-controlled M2 protein from Influenza is a critical component of the virus, serving as a target for aminoadamantane anti-flu 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 FTIR spectroscopy was utilized to measure the precise orientation of the backbone carbonyl groups, and 2D-IR spectroscopy was utilized to identify channel-lining residues. At low pH (open-state), our results match previously published ss-NMR and X-ray structures remarkably well. However, at neutral pH (closed-state), our measurements point to a large conformational change, that is consistent with the transmembrane α -helices rotating by one amino acid register: a structural rearrangement not previously observed. The combination of isotope-labelled FTIR and 2D-IR spectroscopies, alongside simulations, provides a non-invasive mean of interrogating structures of membrane proteins in general and ion channels in particular.