Cholesterol plays a decisive role in tetraspanin assemblies during bilayer deformations

The tetraspanin family plays key roles in many physiological processes, such as, tumour invasion, cell motility, virus infection, cell attachment and entry. Tetraspanins function as molecular scaffolds organized in microdomains with interesting downstream cellular consequences. However, despite their relevance in human physiology, the precise mechanisms of their various functions remain elusive. In particular, the full-length CD81 tetraspanin has interesting cholesterol-related properties that modulate its activity in cells. In this work, we study the opening transition of CD81 under different conditions. We propose that such conformational change is a collaborative process enhanced by simultaneous interactions between multiple identical CD81 tetraspanins. With molecular dynamics simulations we describe the crucial role of a ternary lipid bilayer with cholesterol in CD81 conformational dynamics, observing two emergent properties: first, clusters of CD81 collectively segregate one tetraspanin while favouring one opening transition, second, cumulative cholesterol sequestering by CD81 tetraspanins inhibits large membrane deformations due to local density variations.