Cholesterol sensing by CD81 is important for hepatitis C virus entry

Autor: Stefan Ebner, Piya Mandal, Machaela Palor, María Pía Alberione, Gisa Gerold, Jared Kirui, Annasara Lenman, Rebecca Moeller, Lenka Stejskal, Joe Grove, Adrian J. Shepherd, Felix Meissner
Přispěvatelé: TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany.
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
viruses
Hepacivirus
virus entry
plasma membrane
medicine.disease_cause
Biochemistry
Interactome
Mice
Cricetinae
Receptor
cholesterol-binding protein
biology
Chemistry
Cholesterol binding
Biochemistry and Molecular Biology
Hepatitis C virus (HCV)
Hepatitis C
3. Good health
Cell biology
Cholesterol
Receptors
Virus
Protein Structural Elements
Protein folding
lipids (amino acids
peptides
and proteins)
Hepatitis C virus
Allosteric regulation
Mutagenesis (molecular biology technique)
Context (language use)
chemical and pharmacologic phenomena
bcs
Microbiology
CD19
Cell Line
Tetraspanin 28
03 medical and health sciences
Viral entry
Extracellular
medicine
Animals
Humans
Molecular Biology
030102 biochemistry & molecular biology
Cell Biology
Virus Internalization
biochemical phenomena
metabolism
and nutrition
In vitro
biological factors
molecular dynamics
030104 developmental biology
tetraspanin
Chaperone (protein)
Mutagenesis
Site-Directed
biology.protein
hepatitis C virus (HCV)
Biokemi och molekylärbiologi
CD81
Zdroj: The Journal of biological chemistry
United States
The Journal of Biological Chemistry
ISSN: 0021-9258
Popis: CD81 plays a central role in a variety of physiological and pathological processes. Recent structural analysis of CD81 indicates that it contains an intramembrane cholesterol-binding pocket and that interaction with cholesterol may regulate a conformational opening of the large extracellular domain of CD81. Therefore, CD81 possesses a potential cholesterol sensing mechanism; however, the relevance of this for protein function is thus far unknown. In this study we investigate CD81 cholesterol sensing in the context of its activity as a receptor for hepatitis C virus (HCV). Structure-led mutagenesis of the cholesterol-binding pocket reduced CD81-cholesterol association, but had disparate effects on HCV entry, both reducing and enhancing CD81 receptor activity. We reasoned that this could be explained by alterations in the consequences of cholesterol binding. To investigate this further we performed molecular dynamic simulations of CD81 with and without cholesterol; this identified a potential allosteric mechanism by which cholesterol binding regulates the conformation of CD81. To test this, we designed further mutations to force CD81 into either the open (cholesterol unbound) or closed (cholesterol bound) conformation. The open mutant of CD81 exhibited reduced receptor activity whereas the closed mutant enhanced activity. These data are consistent with CD81 cholesterol sensing resulting in a switch between a receptor active and inactive state. CD81 interactome analysis also suggests that conformational switching may modulate the assembly of CD81-partner protein networks. This work furthers our understanding of the molecular mechanism of CD81 cholesterol sensing, how this relates to HCV entry and CD81’s function as a molecular scaffold; these insights are relevant to CD81’s varied roles in both health and disease.
Databáze: OpenAIRE
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