Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel

Jonathan K. Williams, Daniel Tietze, Myungwoon Lee, Jun Wang, Mei Hong

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Together with the influenza A virus, influenza B virus causes seasonal flu epidemics. The M2 protein of influenza B (BM2) forms a tetrameric proton-conducting channel that is important for the virus lifecycle. BM2 shares little sequence homology with AM2, except for a conserved HxxxW motif in the transmembrane (TM) domain. Unlike AM2, no antiviral drugs have been developed to block the BM2 channel. To elucidate the proton-conduction mechanism of BM2 and to facilitate the development of BM2 inhibitors, we have employed solid-state NMR spectroscopy to investigate the conformation, dynamics, and hydration of the BM2 TM domain in lipid bilayers. BM2 adopts an α-helical conformation in lipid membranes. At physiological temperature and low pH, the proton-selective residue, His19, shows relatively narrow 15N chemical exchange peaks for the imidazole nitrogens, indicating fast proton shuttling that interconverts cationic and neutral histidines. Importantly, pH-dependent 15N chemical shifts indicate that His19 retains the neutral population to much lower pH than His37 in AM2, indicating larger acid-dissociation constants or lower pKa's. We attribute these dynamical and equilibrium differences to the presence of a second titratable histidine, His27, which may increase the proton-dissociation rate of His19. Two-dimensional 1H-13C correlation spectra probing water 1H polarization transfer to the peptide indicates that the BM2 channel becomes much more hydrated at low pH than at high pH, particularly at Ser12, indicating that the pore-facing serine residues in BM2 mediate proton relay to the proton-selective histidine.

Original languageEnglish (US)
Pages (from-to)8143-8155
Number of pages13
JournalJournal of the American Chemical Society
Volume138
Issue number26
DOIs
StatePublished - Jul 6 2016

Fingerprint

Influenza B virus
Viruses
Hydration
Conformations
Protons
Nuclear magnetic resonance
Histidine
Facings
Lipid bilayers
Influenza A virus
Chemical shift
Lipid Bilayers
Membrane Lipids
Sequence Homology
Serine
Human Influenza
Peptides
Nuclear magnetic resonance spectroscopy
Antiviral Agents
Magnetic Resonance Spectroscopy

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Solid-State NMR Investigation of the Conformation, Proton Conduction, and Hydration of the Influenza B Virus M2 Transmembrane Proton Channel. / Williams, Jonathan K.; Tietze, Daniel; Lee, Myungwoon; Wang, Jun; Hong, Mei.

In: Journal of the American Chemical Society, Vol. 138, No. 26, 06.07.2016, p. 8143-8155.

Research output: Contribution to journalArticle

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