Protein-protein interactions at the tight junctions interface.

Abstract

The epithelial and endothelial tissues are the physiological barriers against chemical and biological insurgents by constituting the tight junctions. Tight junctions are specialized adhesion constructs formed by the assembly of claudin family proteins. Membrane-embedded claudin proteins are the functional determinants of the tight junctions. In the paracellular space between two adjacent cells, claudins form size and charge selective pores that impede the free diffusion of these solutes. The vital role of tight junctions in various tissue barriers such as the blood-brain barrier, renal barrier, and gut barrier are currently active research fields, yet a complete molecular understanding of the tight junctions is elusive. Here we have employed multiscale molecular dynamics simulations to gain insight into the underpinnings of claudin assembly at tight junctions. From these simulations, a clear picture of how the membrane milieu influences the tight junction's assembly is evident. Both cholesterol and ceramide lipids limit claudin-claudin interaction in the lipid bilayer due to reduced fluidity. Further, we demonstrated that claudins preferentially assemble into distinct dimers that are the primary building blocks of the paracellular pores. The molecular-level insights gained from this work are critical in unraveling the physiological roles of tight junctions.