ZOproteiner

ZOproteiner, commonly referred to as ZO proteins, are a family of tight junction scaffold proteins found in epithelial and endothelial cells. In vertebrates they are encoded by the TJP gene family and belong to the membrane-associated guanylate kinase (MAGUK) superfamily, comprising ZO-1 (TJP1), ZO-2 (TJP2) and ZO-3 (TJP3). The proteins share a multidomain architecture with three PDZ domains, an SH3 domain and a guanylate kinase-like (GUK) domain. They localize to the cytoplasmic face of tight junctions and link transmembrane components to the underlying actin cytoskeleton.

Functionally, ZO proteins act as central organizers of the tight junction complex. They contribute to the assembly and maintenance of tight junctions, regulate paracellular permeability, and help establish and preserve apical-basal cell polarity. Their presence influences the dynamic remodeling of junctions in response to developmental cues, mechanical stress, and signaling events.

ZO proteins operate as signaling scaffolds. Through their PDZ, SH3, and GUK domains they interact with transmembrane tight junction proteins such as occludin and claudins, as well as with cytoskeletal and signaling partners. phosphorylation and other post-translational modifications modulate their interactions and junctional dynamics, enabling responsive regulation of barrier properties.

Clinical and physiological relevance is tied to barrier integrity. Proper ZO protein function is essential for controlling paracellular flux; dysfunction or mislocalization can accompany inflammatory diseases, tissue injury, and cancer progression through altered barrier function and cell polarity.

Evolutionarily, ZO proteins are highly conserved in vertebrates, with three paralogs arising from gene duplication. Their core role as tight junction scaffolds is preserved across species, underscoring their importance in epithelial and endothelial barriers.