Paracellular ion transport in claudin-15 ion channels.

Abstract

Claudins, one of the primary constituents of tight junctions, assemble to form paracellular channels that regulate ion permeability. From the resolution of its crystallographic structure emerged the opportunities to investigate how structural properties of the pore determine function. In claudin-15, a cation-selective channel in the small intestine, the ion conduction pores are composed of the assembly of four β-sheets from extracellular domains of claudins between two membranes. We used computational methods to map the effect of mutation of the pore-facing residues on charge- and size-selectivity of claudin-15. Utilizing molecular dynamics simulations of a three-pore system in an infinitely long claudin strand, an electric field was applied to induce ion transport. Single pore ion conductance was calculated and the charge-selectivity of the pore was compared against experimental permeability of claudin-15. More than ten single-point and double-point mutations were identified that affect the charge (cation) selectivity of the pore. Coupled with structural variation of the pore, our results elucidate the structural basis for claudin-15 permselectivity.