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 α-helical CD81 large-extracellular-loop domain (CD81_LEL) 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 CD81_LEL plasticity has remained elusive so far.

Here, by combining molecular dynamics simulations and circular dichroism experiments on wt-CD81_LEL 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 CD81_LEL. 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 CD81_LEL. 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 CD81_LEL domain. This mechanism might play a role in other cellular receptors that function along the endosomal pathway.