Membrane Guided Self-Assembly of Dimers and Trimers of Tight Junction Proteins

Tight junctions (TJ) constituted by the claudin family of transmembrane proteins determine solute permeability in the paracellular space of various tissues. Multimeric aggregation of the claudin tight junction strands is difficult to probe using experimental methods. However, understanding how the membrane environment guides the claudin-claudin interactions into TJ assembly has far-reaching significance to a range of biochemical, mechanistic and physiological processes. In this study, we have employed molecular simulations to probe the membrane-driven self-assembly of cis interactions in seven prototypic classic claudins. Hydrophobic mismatch between the transmembrane domains and the bulk lipid medium initiates polymerization that leads to dimeric, trimeric, and higher order assemblies. There are both conformational and morphological differences between individual claudins. Specifically in the case of claudin-2, we observed dimeric conformations that are potentially the cation channel forming dimer, which is important for cation absorption in the kidneys. Furthermore, trimeric assemblies were observed in claudin-2, -4 and -19 that match with the receptor configurations for trimeric Clostridium perfringens enterotoxin (CPE), revealing the potential mechanism for pathogenesis. These important findings observed in the long-timescale self-assembly simulations provide unprecedented molecular level clues about the tight junction architecture.