Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 49, Pages 19994-19999Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1213801109
Keywords
conformational ensemble; dynamics; membrane proteins; RDC; relaxation dispersion
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mass spectrometry facility
- National Institutes of Health (NIH) Intramural Research Programs of the NIDDK
- Center for Information Technology
- Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH
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The highly conserved first 23 residues of the influenza hemagglutinin HA2 subunit constitute the fusion domain, which plays a pivotal role in fusing viral and host-cell membranes. At neutral pH, this peptide adopts a tight helical hairpin wedge structure, stabilized by aliphatic hydrogen bonding and charge-dipole interactions. We demonstrate that at low pH, where the fusion process is triggered, the native peptide transiently visits activated states that are very similar to those sampled by a G8A mutant. This mutant retains a small fraction of helical hairpin conformation, in rapid equilibrium with at least two open structures. The exchange rate between the closed and open conformations of the wild-type fusion peptide is similar to 40 kHz, with a total open-state population of similar to 20%. Transitions to these activated states are likely to play a crucial role in formation of the fusion pore, an essential structure required in the final stage of membrane fusion.
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