Claudin-10b cation channels in tight junction strands: Octameric-interlocked pore barrels constitute paracellular channels with low water permeability

Claudin proteins constitute the backbone of tight junctions (TJs) regulating paracellular permeability for solutes and water. The molecular mechanism of claudin polymerization and paracellular channel formation is unclear. However, a joined double-rows architecture of claudin strands has been supported by experi-mental and modeling data. Here, we compared two variants of this architectural model for the related but functionally distinct cation channel-forming claudin-10b and claudin-15: tetrameric-locked-barrel vs octa-meric-interlocked-barrels model. Homology modeling and molecular dynamics simulations of double -membrane embedded dodecamers indicate that claudin-10b and claudin-15 share the same joined double -rows architecture of TJ-strands. For both, the results indicate octameric-interlocked-barrels: Sidewise un-sealed tetrameric pore scaffolds interlocked with adjacent pores via the beta 1 beta 2 loop of the extracellular segment (ECS) 1. This loop mediates hydrophobic clustering and, together with ECS2, cis- and trans -inter-action between claudins of the adjacent tetrameric pore scaffolds. In addition, the beta 1 beta 2 loop contributes to lining of the ion conduction pathway. The charge-distribution along the pore differs between claudin-10b and claudin-15 and is suggested to be a key determinant for the cation-and water permeabilities that differ between the two claudins. In the claudin-10b simulations, similar as for claudin-15, the conserved D56 in the pore center is the main cation interaction site. In contrast to claudin-15 channels, the claudin-10b-specific D36, K64 and E153 are suggested to cause jamming of cations that prevents efficient water passage. In sum, we provide novel mechanistic information about polymerization of classic claudins, formation of embedded channels and thus regulation of paracellular transport across epithelia.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creative-commons.org/licenses/by-nc-nd/4.0/).

Automated summary

Claudin proteins are crucial for regulating paracellular permeability in tight junctions. The architectural models of claudin-10b and claudin-15 suggest an octameric-interlocked-barrels structure, which contributes to their functional differences in ion and water permeability.