Atomic structures of closed and open influenza B M2 proton channel reveal the conduction mechanism

• Published in: Nature structural & molecular biology Vol. 27; no. 2; pp. 160 - 167
• Main Authors: Mandala, Venkata S., Loftis, Alexander R., Shcherbakov, Alexander A., Pentelute, Bradley L., Hong, Mei
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2020; Nature Publishing Group
• Subjects: 631/326/596; 631/45/269; 631/535/878/1264; Activation; Betainfluenzavirus - chemistry; Betainfluenzavirus - metabolism; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Chain dynamics; Channel gating; Conduction; Domains; Helices; Histidine; Humans; Hydrogen-Ion Concentration; Influenza; Influenza A; Influenza B; Influenza, Human - metabolism; Influenza, Human - virology; Ion Channels - chemistry; Ion Channels - metabolism; Life Sciences; Membrane Biology; Models, Molecular; Molecular conformation; NMR; Nuclear magnetic resonance; Phospholipids; Phospholipids - metabolism; Protein Conformation; Protein Domains; Protein Structure; Proton conduction; Protons; Solid state; Tryptophan; Uncoating; Viral Proteins - chemistry; Viral Proteins - metabolism; Viruses
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-019-0371-2

The influenza B M2 (BM2) proton channel is activated by acidic pH to mediate virus uncoating. Unlike influenza A M2 (AM2), which conducts protons with strong inward rectification, BM2 conducts protons both inward and outward. Here we report 1.4- and 1.5-Å solid-state NMR structures of the transmembrane domain of the closed and open BM2 channels in a phospholipid environment. Upon activation, the transmembrane helices increase the tilt angle by 6° and the average pore diameter enlarges by 2.1 Å. BM2 thus undergoes a scissor motion for activation, which differs from the alternating-access motion of AM2. These results indicate that asymmetric proton conduction requires a backbone hinge motion, whereas bidirectional conduction is achieved by a symmetric scissor motion. The proton-selective histidine and gating tryptophan in the open BM2 reorient on the microsecond timescale, similar to AM2, indicating that side chain dynamics are the essential driver of proton shuttling. Solid-state NMR structures of the influenza B M2 (BM2) proton channel transmembrane domain in a phospholipid environment reveal open and closed conformations and indicate that side chain dynamics are essential for proton shuttling by BM2.