A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction

Abstract

An alternative splice in TOCA-1 targets it to tight junctions. KO of TOCA-1 results in increased flux and decreased tight junction membrane dynamics. Ultrastructural analysis shows actin accumulation at the adherens junction. Identification of the ZO-1/TOCA-1 complex provides insights into tight junction barrier dependence on the dynamic nature of cell–cell contacts and junctional actin.

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…The PDZ containing proteins have one or more PDZ motifs (90-100 amino acids) which are involved in interactions with the C-termini of transmembrane proteins, leading to their clustering and anchoring, and other cytoplasmic TJ proteins and actin filaments which have roles in bringing together the cytoskeleton, signaling and integral proteins at specific regions of the plasma membrane. [40][41][42][43] The TJ PDZ scaffolding proteins include members of a family of membrane associated guanylate kinases (MAGUK), zonula occludens ¡1, ¡2 and 3 (ZO-1, ZO-2 and ZO-3). ZO proteins share 3 core regions: a SH3 domain important for binding signaling proteins and cytoskeletal elements, a guanylate cyclase, involved in catalyzing the ATP-dependent transformation of GMP to GDP and PDZ domains that bind to the C-terminal cytoplasmic ends of transmembrane proteins.…”

“…The PDZ2 domain is the place of ZO-1 dimerization, interaction with ZO-2 (ZO-1/ZO-2 heterodimer) and Cx43 binding, establishing a link with gap junctions. 41,42,[44][45][46] The ZO-1 C-terminus contains the actin-binding region (ABR) which is necessary and sufficient for interaction with F-actin. 42,45 Adherens junction proteins, via a-catenin, bind to the N-terminus of ZO-1.…”

“…They affect the association of the actin cytoskeleton with TJ scaffolding proteins, particularly ZO-1, representing a bridging structure between scaffolding proteins and actin microfilaments. 42,47 Among the actin polymerizing proteins associated with TJs and expressed in brain endothelial cells are Arp2/3, cortactin and VASP. [64][65][66] The regulation of actin organization and trafficking is mediated by RhoA GTPases (RhoA, Cdc42 and Rac) and the Rab family of proteins and these proteins are closely associated with TJ complex acting via their exchanging factors as scaffolding proteins.…”

Contributions of intestinal epithelial barriers to health and disease

“…Further insights into potential mechanisms by which molecular interactions regulate tight junctions come from recent studies that identified TOCA-1 (transducer of cdc42-dependent actin activity) as a ZO-1 binding protein [42,43]. TOCA-1 trafficking to the tight junction requires interactions with the ZO-1 PDZ1 domain.…”

Efficient genome editing of differentiated renal epithelial cells

“…Indeed, genome edited renal epithelial cells have been successfully used to study renal epithelial physiology [e.g. 26, 29]. However, the practical implementation of required genome engineering technologies has been challenging for many laboratories.…”