Crystal Structure of a Claudin Provides Insight into the Architecture of Tight Junctions

Abstract

Tight junctions are cell-cell adhesion structures in epithelial cell sheets that surround organ compartments in multicellular organisms and regulate the permeation of ions through the intercellular space. Claudins are the major constituents of tight junctions and form strands that mediate cell adhesion and function as paracellular barriers. We report the structure of mammalian claudin-15 at a resolution of 2.4 angstroms. The structure reveals a characteristic β-sheet fold comprising two extracellular segments, which is anchored to a transmembrane four-helix bundle by a consensus motif. Our analyses suggest potential paracellular pathways with distinctive charges on the extracellular surface, providing insight into the molecular basis of ion homeostasis across tight junctions.

Claudin-21 Has a Paracellular Channel Role at Tight Junctions

“…To verify claudin-21's ion selectivity, we built homology models of claudin-21 based on the crystal structure of claudin-15 (25). We also built structural models of claudin-2 and -10a, as channels with a preference for positively and negatively charged ions, respectively.…”

“…Two categories of claudins have been proposed, namely, the paracellular barrier type and the paracellular channel type, based on the transepithelial electrical resistance (TER) or on the cation and/or anion permeability of many epithelial cell lines (5, 7). Among some claudins characterized as channel-type claudins, such as claudin-2, -7, -10, -15, -16, and -17, claudin-2 and -15 have been studied extensively with respect to specific ions and water (9-11, 14, 17, 20, 21, 23, 24).The structure of claudin-15 was recently analyzed; this analysis revealed that two extracellular segments form a unique ␤ sheet domain fixed to a transmembrane four-helix bundle by a W-LW claudin consensus motif (25,26). The high-resolution structure of claudin-15 suggests that a ␤-barrel pore created by eight claudin molecules in the region between two cells can form a paracellular channel, which is regulated by charged residues on the claudins' extracellular domains.…”

“…The structure of claudin-15 was recently analyzed; this analysis revealed that two extracellular segments form a unique ␤ sheet domain fixed to a transmembrane four-helix bundle by a W-LW claudin consensus motif (25,26). The high-resolution structure of claudin-15 suggests that a ␤-barrel pore created by eight claudin molecules in the region between two cells can form a paracellular channel, which is regulated by charged residues on the claudins' extracellular domains.…”

The mucosal barrier at a glance

“…Claudin-2 pores also permit the flux of water through a common pore (Muto et al, 2010;Rosenthal et al, 2016Rosenthal et al, , 2010. The specificity for Na + is governed by the first of two extracellular loops of claudin-2 that are adjoined to four transmembrane domains with intracellular N-and C-termini Li et al, 2014;Suzuki et al, 2014;Yu et al, 2009). Pore-forming claudins define the charge and size selectivity of the high-capacity pore pathway Colegio et al, 2002;Shen et al, 2011;Turner, 2009;Van Itallie et al, 2008;Weber et al, 2010).…”

Control of AMPA Receptor Activity by the Extracellular Loops of Auxiliary Proteins

“…Crystal structures of Claudins, proteins with close homology to TARPs, enabled a more refined view, defining a folded extracellular 'cap' (Suzuki et al, 2014;Saitoh et al, 2015;Shinoda et al, 2016) that substantially limits the sections of the extracellular portion of TARPs that are able to interact with the AMPA receptor, and therefore the likely range of these interactions. More recently, cryo-EM/single particle analysis of GluA2-TARP complexes allowed unambiguous positioning of TARPs at the periphery of the GluA2 pore, and partially resolved the extracellular domains of TARPs (Twomey et al, 2016;Zhao et al, 2016).…”