Gating Mechanism of the Influenza A M2 Channel Revealed by 1D and 2D IR Spectroscopies

Joshua Manor, Prabuddha Mukherjee, Yu Shan Lin, Hadas Leonov, James L. Skinner*, Martin T. Zanni, Isaiah T. Arkin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

110 Scopus citations

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 α-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.

Original languageAmerican English
Pages (from-to)247-254
Number of pages8
JournalStructure
Volume17
Issue number2
DOIs
StatePublished - 13 Feb 2009

Bibliographical note

Funding Information:
We thank W.F. DeGrado for thoughtful discussions. This work was supported in part by grants from the National Institutes of Health (R21AI064797 to M.T.Z. and I.T.A.), the National Science Foundation (CHE-0832584 to J.L.S. and M.T.Z.), and the Israeli Science Foundation (784/01, 1249/05, and 1581/08 to I.T.A.). J.L.S. thanks the National Science Foundation (CHE-0750307) for support. I.T.A. is the Arthur Lejwa Professor of Structural Biochemistry at the Hebrew University of Jerusalem. Molecular figures were generated by PyMOL (DeLano Scientific, LLC, San Francisco).

Keywords

  • PROTEINS

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