دورية أكاديمية
Reversible structural changes in the influenza hemagglutinin precursor at membrane fusion pH.
| العنوان: | Reversible structural changes in the influenza hemagglutinin precursor at membrane fusion pH. |
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| المؤلفون: | Garcia-Moro E; Structural Biology of Cells and Viruses Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Zhang J; Structural Biology of Disease Processes Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Calder LJ; Structural Biology of Cells and Viruses Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Brown NR; Structural Biology of Disease Processes Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Gamblin SJ; Structural Biology of Disease Processes Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Skehel JJ; Structural Biology of Disease Processes Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom., Rosenthal PB; Structural Biology of Cells and Viruses Laboratory, Francis Crick Institute, NW1 AT London, United Kingdom. |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2022 Aug 16; Vol. 119 (33), pp. e2208011119. Date of Electronic Publication: 2022 Aug 08. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Hemagglutinin Glycoproteins, Influenza Virus*/chemistry , Membrane Fusion* , Orthomyxoviridae*/physiology , Virus Internalization*, Humans ; Hydrogen-Ion Concentration ; Protein Conformation |
| مستخلص: | The subunits of the influenza hemagglutinin (HA) trimer are synthesized as single-chain precursors (HA0s) that are proteolytically cleaved into the disulfide-linked polypeptides HA1 and HA2. Cleavage is required for activation of membrane fusion at low pH, which occurs at the beginning of infection following transfer of cell-surface-bound viruses into endosomes. Activation results in extensive changes in the conformation of cleaved HA. To establish the overall contribution of cleavage to the mechanism of HA-mediated membrane fusion, we used cryogenic electron microscopy (cryo-EM) to directly image HA0 at neutral and low pH. We found extensive pH-induced structural changes, some of which were similar to those described for intermediates in the refolding of cleaved HA at low pH. They involve a partial extension of the long central coiled coil formed by melting of the preexisting secondary structure, threading it between the membrane-distal domains, and subsequent refolding as extended helices. The fusion peptide, covalently linked at its N terminus, adopts an amphipathic helical conformation over part of its length and is repositioned and packed against a complementary surface groove of conserved residues. Furthermore, and in contrast to cleaved HA, the changes in HA0 structure at low pH are reversible on reincubation at neutral pH. We discuss the implications of covalently restricted HA0 refolding for the cleaved HA conformational changes that mediate membrane fusion and for the action of antiviral drug candidates and cross-reactive anti-HA antibodies that can block influenza infectivity. |
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| معلومات مُعتمدة: | FC001078 United Kingdom CRUK_ Cancer Research UK; FC001078 United Kingdom MRC_ Medical Research Council; FC001078 United Kingdom WT_ Wellcome Trust; FC001143 United Kingdom CRUK_ Cancer Research UK; FC001143 United Kingdom MRC_ Medical Research Council; FC001143 United Kingdom WT_ Wellcome Trust; 219946/Z/19/Z United Kingdom WT_ Wellcome Trust |
| فهرسة مساهمة: | Keywords: cryo-EM; hemagglutinin; influenza; membrane fusion; protein folding |
| المشرفين على المادة: | 0 (Hemagglutinin Glycoproteins, Influenza Virus) |
| تواريخ الأحداث: | Date Created: 20220808 Date Completed: 20220810 Latest Revision: 20220930 |
| رمز التحديث: | 20221213 |
| مُعرف محوري في PubMed: | PMC9388137 |
| DOI: | 10.1073/pnas.2208011119 |
| PMID: | 35939703 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.2208011119 |