Structure of the tetraspanin main extracellular domain - A partially conserved fold with a structurally variable domain insertion

The tetraspanin family of membrane glycoproteins is involved in the regulat ion of cellular development, proliferation, activation, and mobility. We ha ve attempted to predict the structural features of the large extracellular domain of tetraspanins (EC2), which is very important in determining their functional specificity. The tetraspanin EC2 is composed of two subdomains: a conserved three-helix subdomain and a variable secondary structure subdom ain inserted within the conserved subdomain. The occurrence of key disulphi de bridges and other invariant residues leads to a conserved relative topol ogy of both subdomains and also suggests a structural classification of tet raspanins. Using the CD81 EC2 structure as a template, the structures of tw o other EC2s were predicted by homology modeling and indicate a conserved s hape, in which the variable subdomain is located at one side of the structu re. The conserved and variable subdomains might contain sites that correspo nd, respectively, to common and specific interactions of tetraspanins. The tetraspanin EC2 seems to correspond to a new scheme of fold conservation/va riability among proteins, namely the insertion of a structurally variable s ubdomain within an otherwise conserved fold.