An entropic safety catch controls hepatitis C virus entry and antibody resistance
| Autor: | David S. Moss, Myrto Kremyda-Vlachou, Lucas Walker, Machaela Palor, Tina Daviter, Joe Grove, William Rosenberg, William D. Lees, Christopher J. R. Illingworth, Lenka Stejskal, Zisis Kozlakidis, Mphatso D Kalemera, Adrian J. Shepherd |
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| Přispěvatelé: | Kalemera, Mphatso D [0000-0001-9461-1117], Bailey, Dalan [0000-0002-5640-2266], Rosenberg, William [0000-0002-2732-2304], Illingworth, Christopher [0000-0002-0030-2784], Shepherd, Adrian J [0000-0003-0194-8613], Grove, Joe [0000-0001-5390-7579], Apollo - University of Cambridge Repository, Illingworth, Christopher JR [0000-0002-0030-2784] |
| Rok vydání: | 2022 |
| Předmět: |
Hepatitis C virus
Structural Biology and Molecular Biophysics infectious disease Entropy Cell Hepacivirus virus entry bcs medicine.disease_cause Virus General Biochemistry Genetics and Molecular Biology Viral Envelope Proteins Viral entry medicine molecular biophysics antibodies structural biology Humans viruses Receptor protein disorder Microbiology and Infectious Disease biology General Immunology and Microbiology Chemistry General Neuroscience microbiology General Medicine Conformational entropy hepatitis c virus Virus Internalization Virology Antibodies Neutralizing Hepatitis C molecular dynamics medicine.anatomical_structure biology.protein Antibody Function (biology) Research Article |
| ISSN: | 2050-084X |
| DOI: | 10.17863/cam.87356 |
| Popis: | E1 and E2 (E1E2), the fusion proteins of Hepatitis C Virus (HCV), are unlike that of any other virus yet described, and the detailed molecular mechanisms of HCV entry/fusion remain unknown. Hypervariable region-1 (HVR-1) of E2 is a putative intrinsically disordered protein tail. Here, we demonstrate that HVR-1 has an autoinhibitory function that suppresses the activity of E1E2 on free virions; this is dependent on its conformational entropy. Thus, HVR-1 is akin to a safety catch that prevents premature triggering of E1E2 activity. Crucially, this mechanism is turned off by host receptor interactions at the cell surface to allow entry. Mutations that reduce conformational entropy in HVR-1, or genetic deletion of HVR-1, turn off the safety catch to generate hyper-reactive HCV that exhibits enhanced virus entry but is thermally unstable and acutely sensitive to neutralising antibodies. Therefore, the HVR-1 safety catch controls the efficiency of virus entry and maintains resistance to neutralising antibodies. This discovery provides an explanation for the ability of HCV to persist in the face of continual immune assault and represents a novel regulatory mechanism that is likely to be found in other viral fusion machinery. |
| Databáze: | OpenAIRE |
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