Giuseppe
Emeritus
[Source: Proceedings of the National Academy of the Sciences of the United States of America, full pate: (LINK). Abstract, edited.]
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pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR
Justin L. Lorieau <SUP>a</SUP>, John M. Louis<SUP>a</SUP>, Charles D. Schwieters<SUP>b</SUP>, and Adriaan Bax<SUP>a</SUP>,<SUP>1</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases; and <SUP>b</SUP>Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892
Edited by William F. DeGrado, UCSF School of Pharmacy, University of California, San Francisco, CA, and approved October 19, 2012 (received for review August 10, 2012)
Abstract
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 ∼40 kHz, with a total open-state population of ∼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.
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: bax@nih.gov.
Author contributions: J.L.L., J.M.L., and A.B. designed research; J.L.L. and J.M.L. performed research; J.M.L. and C.D.S. contributed new reagents/analytic tools; J.L.L. analyzed data; and J.L.L. and A.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and restraints have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2LWA); and NMR chemical shifts have been deposited in the BioMagResBank, www.bmrb.wisc.edu (accession no. 18617).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213801109/-/DCSupplemental.
Freely available online through the PNAS open access option.
-<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases; and <SUP>b</SUP>Division of Computational Bioscience, Center for Information Technology, National Institutes of Health, Bethesda, MD 20892
Edited by William F. DeGrado, UCSF School of Pharmacy, University of California, San Francisco, CA, and approved October 19, 2012 (received for review August 10, 2012)
Abstract
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 ∼40 kHz, with a total open-state population of ∼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.
- conformational ensemble
- dynamics
- membrane proteins
- RDC
- relaxation dispersion
<SUP>1</SUP>To whom correspondence should be addressed. E-mail: bax@nih.gov.
Author contributions: J.L.L., J.M.L., and A.B. designed research; J.L.L. and J.M.L. performed research; J.M.L. and C.D.S. contributed new reagents/analytic tools; J.L.L. analyzed data; and J.L.L. and A.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates and restraints have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2LWA); and NMR chemical shifts have been deposited in the BioMagResBank, www.bmrb.wisc.edu (accession no. 18617).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1213801109/-/DCSupplemental.
Freely available online through the PNAS open access option.
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