Solvent-induced allosteric transition of the Hepatitis C virus human cellular receptor CD81 large extracellular loop

Abstract

CD81 is a tetraspanin receptor that clusters into microdomains to mediate cell signalling processes. CD81 is also one of the four primary cellular receptors of the Hepatitis C virus (HCV). Previous structural studies on the -helical CD81 large-extracellular-loop domain (CD81LEL) have shown that it can adopt different conformations (from closed to open), likely depending on the environmental conditions. This conformational plasticity has been implicated in the endosomal fusion of HCV upon entry. However, the precise mechanism governing the CD81LEL plasticity has remained elusive so far. Here, by combining molecular dynamics simulations and circular dichroism experiments on wt-CD81LEL and two mutants at different endosomal pH conditions, pH 5.5 and pH 4.6, we show that the modulation of the solvation shell governs the plasticity of CD81LEL. The primarily implicated residues are D139 and E188, respectively, located near a loop preceded by a helix. At acidic conditions, their interaction with water is reduced, causing a re-ordering of the water molecules, and thus triggering the dynamics of CD81LEL. However, mutations E188Q and D139N retain the solvation shell and restrict the conformational space that the head subdomain can explore. We propose that residues E188 and D139 control the solvent-induced allosteric transition of the CD81LEL domain. This mechanism might play a role in other cellular receptors that function along the endosomal pathway. Popular SummaryUnderstanding the cellular mechanisms that are exploited by viruses to infect their host is key for the development of therapeutics. Here, in the context of Hepatitis C Virus infection we report the mechanism that governs the plasticity of the extra-cellular domain of tetraspanin CD81, one of the major cellular receptors of this virus. The mechanism proposed here is a novel form of solvent-induced allosteric transition in proteins mediated by two antenna residues located in the head subdomain of CD81. We propose that it could serve as a pH sensing strategy to time the endosomal pathway and trigger a signal at the right time for HCV fusion.