The Claudins: From Tight Junctions to Biological Systems

The claudin protein family, which has 27 members in mammals, consists of tight junction (TJ) proteins that are indispensable for the paracellular barrier in vertebrate epithelial cell sheets. The detailed structures of claudin-15, -19, and -4 were recently solved at the amino acid level, opening the door to research into how claudins form TJ strands and elicit the paracellular barrier and channel functions of TJs. All claudin family members are expected to share the same basic structural framework, including cis- and trans-interactions with each other, but have different extracellular regions that account for their various roles in forming paracellular barriers and channels. Claudin knockout (KO) mouse studies and human variations in claudin expressions provide clues about how various biological systems are robustly and flexibly constructed with respect to claudin-based TJs. Claudins are cell–cell adhesion molecules located at the tight junctions (TJs) between cells in epithelial cell sheets. The claudin family in mammals consists of 27 four-transmembrane domain proteins. Claudins are responsible for the paracellular barrier function of TJs, and in some cases confer paracellular channel functions to the paracellular barriers of TJs. Based on recent breakthroughs in the molecular structure of claudins, the hypothetical ‘antiparallel double row model’ was proposed, which suggests how claudins polymerize in a linear fashion and form TJ strands with paracellular barrier and channel functions. Meanwhile, ongoing studies at the cell and tissue levels are clarifying how the paracellular barrier and/or channel functions of claudin-based TJs, which are both robust and flexible, organize various biological systems. Claudins are cell–cell adhesion molecules located at the tight junctions (TJs) between cells in epithelial cell sheets. The claudin family in mammals consists of 27 four-transmembrane domain proteins. Claudins are responsible for the paracellular barrier function of TJs, and in some cases confer paracellular channel functions to the paracellular barriers of TJs. Based on recent breakthroughs in the molecular structure of claudins, the hypothetical ‘antiparallel double row model’ was proposed, which suggests how claudins polymerize in a linear fashion and form TJ strands with paracellular barrier and channel functions. Meanwhile, ongoing studies at the cell and tissue levels are clarifying how the paracellular barrier and/or channel functions of claudin-based TJs, which are both robust and flexible, organize various biological systems. claudins (∼22 kD) and cadherins (∼124 kD) are cell–cell adhesion molecules of the TJ and adherens junction (AJ), with four and one membrane-spanning regions, respectively. The polymerization of claudins, of which there are 27 family members in mammals, is indispensable for the formation of TJ strands and the paracellular barrier functions of the TJ. Cadherins (almost 17 members of classical cadherins are reported in mammals) have a central role in cell–cell adhesion. the paracellular barrier is constructed by TJs, which block the passage of ions and solutes between epithelial cells. The TJ paracellular barrier is not a simple barrier, but is a sophisticated permselective barrier with context-dependent characteristics. for the paracellular permeability at TJs, basically two mechanisms have been proposed: the ‘pore’ pathway, in which solutes pass through a paracellular channel formed in the TJ strands; and the ‘leak’ pathway, in which they supposedly pass through breaks in the TJ strands. in vertebrate epithelial cell sheets, the cell–cell adhesion junctions are composed of the TJ, adherens junction, and desmosome between cells, which are all situated in the apical region of the lateral membranes. Among these structures, the TJ is situated at the most apical part; as a result, the apical surfaces of the epithelial cells are continuously connected by TJs to create the epithelial barrier. The adherens junctions are situated just beneath the TJs in the apical-to-basal direction of the lateral membranes.