pH-antenna residues trigger a large-scale conformational change in the large extracellular loop domain of the CD81...

CD81 is a human receptor that clusters into microdomains to mediate cell signaling processes. Previous structural studies on the CD81 large-extracellular-loop domain (CD81LEL) proposed that its conformation (ranging from closed to open) may depend on environmental pH conditions. However, the precise mechanism governing CD81LEL plasticity has remained unconfirmed until now. Here, by combining molecular dynamics simulations and spectroscopic experiments on CD81LEL, we show that the mechanism underlying the dependence of the changes in pH to the opening of CD81LEL relates to the modulation of the solvation shell by "antenna" residues. The antenna residues are D139 and E188. Under acidic conditions, such residues generate a signal cascade propagating through the CD81LEL molecule changing the local solvation that, in turn, acts as an effector of the closed-to-open conformational transition. We further proved the key role of D139 and E188 by introducing mutations that switch off their sensitivity to pH. As expected, the mutations stabilize the closed conformation. This signal transduction mechanism might play a role in other cellular receptors that function along the endosomal pathway.