Abstract
Tight junctions consist of a network of sealing strands that create selective ion permeability barriers between adjoining epithelial or endothelial cells. The current model for tight junction strands consists of paired rows of claudins (Cldn) coupled by a cis interface (X-1) derived from crystalline Cldn15. Here we show that tight junction strands exhibit a broad range of lateral bending, indicating diversity in cis interactions. By combining protein–protein docking, coevolutionary analysis, molecular dynamics, and a mutagenesis screen, we identify a new Cldn–Cldn cis interface (Cis-1) that shares interacting residues with X-1 but has an ~ 17° lateral rotation between monomers. In addition, we found that a missense mutation in a Cldn14 that causes deafness and contributes stronger to Cis-1 than to X-1 prevents strand formation in cultured cells. Our results suggest that Cis-1 contributes to the inherent structural flexibility of tight junction strands and is required for maintaining permeability barrier function and hearing.
Highlights
Tight junctions consist of a network of sealing strands that create selective ion permeability barriers between adjoining epithelial or endothelial cells
The recently reported crystal structures of the mouse claudin[15] monomer (PDB ID:4P79)[6] and the claudin-19 and claudin-4 complexes with the Clostridium perfringens enterotoxin (CPE) (PDB ID:3 × 29 and 5B2G)[12, 13] have provided structural information to model tight junction strands
This model depends on an axial cis interface (X-1) that involves a hydrophobic interaction between the methionine 68 (M68) on the extracellular helix (ECH) and two phenylalanines (F146 and F147) on ECL26, 9
Summary
Tight junctions consist of a network of sealing strands that create selective ion permeability barriers between adjoining epithelial or endothelial cells. The model contains a medial-cis interaction between the ECL1 β-sheets that was further substantiated by mutagenesis of key residues in this region[11] This model depends on an axial cis interface (X-1) that involves a hydrophobic interaction between the methionine 68 (M68) on the ECH and two phenylalanines (F146 and F147) on ECL26, 9. This double-rowed model is consistent with biochemical analysis of Cldn strands[8, 14] and shows a possible ion permeability mechanism. This study suggests that X-1 and Cis-1 contribute to tight junction strand structural variability and inherent flexibility
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