Structural insights into hepatitis C virus receptor binding and entry.

Area of Science:

• Virology
• Structural Biology
• Cell Biology

Background:

• Hepatitis C virus (HCV) causes chronic liver disease, cirrhosis, and liver cancer, affecting over 70 million globally.
• HCV envelope glycoproteins E1 and E2 mediate viral entry, but the precise mechanism remains unclear.
• Neutralizing antibodies often target the E2 glycoprotein's interaction with the CD81 receptor's large extracellular loop (CD81-LEL).

Purpose of the Study:

• To elucidate the structural and molecular mechanisms of HCV entry.
• To investigate the role of pH and CD81 binding in the interaction between HCV E2 and CD81-LEL.
• To determine the structural basis for E2-mediated membrane fusion.

Main Methods:

• X-ray crystallography was used to determine the structures of E2 complexes.
• Mutagenesis studies were performed on key E2 residues.
• Liposome flotation assays assessed the interaction of E2 with membranes.

Main Results:

• Low pH enhances the binding of CD81-LEL to the E2 glycoprotein.
• Crystal structures revealed conformational changes in E2 upon CD81-LEL binding, displacing residues 418-422 and extending an internal loop (520-539).
• Specific E2 residues (Tyr529, Trp531, Ile422) are crucial for membrane interaction, which is promoted by low pH and CD81-LEL.

Conclusions:

• Acidification and CD81-LEL binding induce a conformational shift in E2.
• This conformational change primes E2 for membrane fusion, representing a key step in HCV entry.
• The findings provide a molecular model for HCV-host cell membrane interaction.