| Autor: |
Palor, Machaela, Stejskal, Lenka, Mandal, Piya, Shepherd, Adrian J., Grove, Joe |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
|
| DOI: |
10.1101/542837 |
| Popis: |
CD81 is a multifunctional protein that plays a central role in both physiological and pathological processes. Recent structural analysis of CD81 indicates that it adopts a compact fold with its large extracellular loop sitting close to the plasma membrane; however, there is evidence that CD81 can undergo a conformational switch where the extracellular loop flips into an extended open conformation. We investigated the relevance of CD81 conformational switching to its function as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis was used to generate CD81 variants with altered conformational switching. Each variant maintained proper protein folding and expression, and retained a basic function: the ability to chaperone CD19 to the cell surface. We then used multiple systems to evaluate HCV receptor activity; in these experiments ‘open’ CD81 variants exhibited consistently poor receptor function, whereas a ‘closed’ CD81 displayed enhanced ability to support HCV entry. We sought to corroborate these findings by exploring CD81 structural flexibility using molecular dynamics simulations. These experiments were in excellent agreement with our in vitro work, with ‘open’ CD81 variants having a propensity to undergo conformational switching. Taken together, we provide evidence for a conformational switch in CD81 that regulates its HCV receptor activity. This work furthers our understanding of the molecular mechanism of HCV entry and is relevant to CD81’s other functions in health and disease. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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