Folding and oligomerization of CLC channels and transporters
Regarded as one of the most complex membrane protein folds, CLCs form a large family of membrane proteins that function as anion channels and secondary active anion/proton transporters. Despite low sequence similarity, available structures are remarkably similar, maintaining the same inverted topology and fold, with subunits assembled as dimers in wild-type structures. Because of these strong structural features, CLC-ec1, a prokaryotic homolog from E. coli, has become a highly valuable model system for studying membrane protein folding and oligomerization assembly. Associating via a membrane-embedded dimerization interface, the subunits participate in a dynamic equilibrium between monomers and dimers in lipid bilayers, enabling investigation of the physical driving forces underlying the formation of stable membrane complexes. Like soluble protein assembly, studies indicate that CLC-ec1 dimerization is driven by a solvophobic force arising from the free energy gained by burying lipid bilayer defects. Dimerization stability is influenced by lipid composition and pH, which, in turn, provide a mechanism for functional regulation through oligomerization. In this review, I provide an overview of how the exploration of CLC folding and oligomerization advances our understanding of membrane protein self-assembly in general and the role of oligomerization in regulating function.