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Tight junctions primarily comprise claudin and occludin transmembrane proteins, each containing four membrane-spanning alpha-helices. These proteins polymerize into rows on the cell membrane, forming sealing strands that attach to similar strands on adjacent cells via their extracellular loops. The overview content also identifies tricellulin and JAM (junctional adhesion molecule) as additional tight junction proteins that contribute to the seal.

Tight junctions seal the paracellular space between epithelial cells, blocking the flow of macromolecules, ions, and small solutes. Claudin and occludin strands form a network that holds adjacent cell membranes together. On the cytoplasmic side, zonula occludens (ZO) scaffold proteins bind to these transmembrane proteins and organize them into a stabilizing mesh that reinforces the seal.

Zonula occludens (ZO) proteins are large scaffold proteins that associate with the C-terminal tails of claudins and occludins through their PDZ domains. ZO proteins contain multiple protein-binding domains, allowing them to bind claudins, occludins, actin, and other ZO proteins. This creates a mesh structure that organizes and stabilizes the sealing strands of tight junctions.

Multiple claudin isoforms confer selective permeability to different tight junctions. For example, claudin-16 in kidney epithelium increases magnesium ion permeability, allowing reuptake from blood during filtration. In contrast, claudin-5 in brain capillary endothelial cells decreases ion permeability across the blood-brain barrier, demonstrating how claudin diversity regulates paracellular transport.

Tricellular junctions seal gaps formed where three cells meet. Unlike bicellular tight junctions between two cells, tricellular sealing strands are oriented perpendicularly, forming a narrow vertical tube approximately 10 nanometers in diameter. This structure controls paracellular movement of molecules at three-cell contact points, with tricellulin protein concentrating at these sites to maintain the seal.

Beyond sealing the paracellular space, tight junctions prevent lateral movement of membrane proteins such as glucose transporters. This restriction localizes these proteins to the apical surface of intestinal epithelium, enabling efficient glucose absorption. The tight junction barrier thus functions as both a seal and a membrane domain organizer.

Tricellulin, the first protein identified at tricellular junctions, shares sequence homology with occludin and has four human isoforms. Mutations in the tricellulin gene (TRIC) cause hearing impairment, demonstrating its importance in maintaining tight seals in specialized structures like the organ of Corti in the inner ear, where precise barrier function is essential.