Abstract
Tight-junctions between epithelial cells of biological barriers are specialized molecular structures that regulate the flux of solutes across the barrier, parallel to cell walls. The tight-junction backbone is made of strands of transmembrane proteins from the claudin family, but the molecular mechanism of its function is still not completely understood. Recently, the crystal structure of a mammalian claudin-15 was reported, displaying for the first time the detailed features of transmembrane and extracellular domains. Successively, a structural model of claudin-15-based paracellular channels has been proposed, suggesting a putative assembly that illustrates how claudins associate in the same cell (via cis interactions) and across adjacent cells (via trans interactions). Although very promising, the model offers only a static conformation, with residues missing in the most important extracellular regions and potential steric clashes. Here we present detailed atomic models of paracellular single and double pore architectures, obtained from the putative assembly and refined via structural modeling and all-atom molecular dynamics simulations in double membrane bilayer and water environment. Our results show an overall stable configuration of the complex with a fluctuating pore size. Extracellular residue loops in trans interaction are able to form stable contacts and regulate the size of the pore, which displays a stationary radius of 2.5–3.0 Å at the narrowest region. The side-by-side interactions of the cis configuration are preserved via stable hydrogen bonds, already predicted by cysteine crosslinking experiments. Overall, this work introduces an improved version of the claudin-15-based paracellular channel model that strengthens its validity and that can be used in further computational studies to understand the structural features of tight-junctions regulation.
Highlights
Biological barriers such as the blood-brain, renal or intestinal barriers are highly complex structures that perform the fundamental task of maintaining stable physical and chemical conditions of the compartments they separate
We explore via all-atom molecular dynamics (MD) simulations different paracellular pore structures made of Cldn15 monomers built starting from the model by Suzuki et al, with the aim of assessing its structural stability and conformational properties
Our results demonstrate that the missing protein segments in the model of Suzuki et al can arrange without clashes in multiple different conformations, and confirm that the structure is a possible arrangement of claudin monomers forming paracellular pores
Summary
Biological barriers such as the blood-brain, renal or intestinal barriers are highly complex structures that perform the fundamental task of maintaining stable physical and chemical conditions of the compartments they separate. They are composed of closely joined epithelial cells. While the mechanisms underlying transcellular permeation are fairly understood, the investigation of paracellular pathways has been hampered by the lack of structural information. This leaves major challenges such as the design of TJ penetrating drugs and nanomaterials unresolved [10]
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