title: Model for the architecture of claudin-based paracellular ion channels through tight junctions.
abstract: Claudins are main cell-cell adhesion molecules of tight junctions (TJs) between cells in epithelial sheets that form tight barriers that separate the apical from the basolateral space but also contain paracellular channels that regulate the flow of ions and solutes in between these intercellular spaces. Recently, the first crystal structure of a claudin was determined, that of claudin-15, which indicated the parts of the large extracellular domains that likely form the pore-lining surfaces of the paracellular channels. However, the crystal structure did not show how claudin molecules are arranged in the cell membrane to form the backbone of TJ strands and to mediate interactions between adjacent cells, information that is essential to understand how the paracellular channels in TJs function. Here, we propose that TJ strands consist of claudin protomers that assemble into antiparallel double rows. This model is based on cysteine crosslinking experiments that show claudin-15 to dimerize face to face through interactions between the edges of the extracellular β-sheets. Strands observed by freeze-fracture electron microscopy of TJs also show that their width is consistent with the dimensions of a claudin dimer. Furthermore, we propose that extracellular variable regions are responsible for head-to-head interactions of TJ strands in adjoining cells, thus resulting in the formation of paracellular channels. Our model of the TJ architecture provides a basis to discuss structural mechanisms underlying the selective ion permeability and barrier properties of TJs.
authors.affiliation: Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Tani
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: atsukia@biosci.med.osaka-u.ac.jp.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Cellular and Structural Physiology Institute, Nagoya University, Chikusa, Nagoya 464-8601, Japan; Department of Basic Medical Science, Graduate School of Pharmaceutical Science, Nagoya University, Chikusa, Nagoya 464-8601, Japan. Electronic address: yoshi@cespi.nagoya-u.ac.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujiyoshi
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D057167:Claudins / Q000737:chemistry* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007473:Ion Channels / Q000737:chemistry*; D008854:Microscopy, Electron; D008958:Models, Molecular; D015394:Molecular Structure; D011401:Promoter Regions, Genetic; D017433:Protein Structure, Secondary; D061987:Sf9 Cells; D018411:Spodoptera; D019108:Tight Junctions / Q000737:chemistry*
chemical_list: D057167:Claudins; D007473:Ion Channels; C459596:claudin 15
keywords: cell adhesion; claudin; ion channels; paracellular transport; tight junctions