The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions.

TLDR

Tight junctions form an intercellular barrier, maintain epithelial polarity, and their paracellular sealing varies among cell types, a process regulated by as yet undefined mechanisms. Human ZO‑1 is a 1,736‑residue protein whose N‑terminal 793 aa are homologous to Drosophila dlg and PSD‑95, and whose 943‑aa proline‑rich C‑terminal domain contains an alternatively spliced region linked to variable tight‑junction properties. The homology of ZO‑1 to dlg and PSD‑95, together with dlg‑mutation phenotypes that abolish polarity and promote neoplastic growth, provide biochemical evidence for a conserved signal‑transduction protein family at intercellular junctions and show that the C‑terminal domain confers junction‑specific functional diversity.

Abstract

Tight junctions form an intercellular barrier between epithelial cells, serve to separate tissue compartments, and maintain cellular polarity. Paracellular sealing properties vary among cell types and are regulated by undefined mechanisms. Sequence of the full-length cDNA for human ZO-1, the first identified tight junction component, predicts a protein of 1736 aa. The N-terminal 793 aa are homologous to the product of the lethal(1)discs-large-1 (dlg) tumor suppressor gene of Drosophila, located in septate junctions, and to a 95-kDa protein located in the postsynaptic densities of rat brain, PSD-95. All three proteins contain both a src homology region 3 (SH3 domain), previously identified in membrane proteins involved in signal transduction, and a region homologous to guanylate kinase. ZO-1 contains an additional 943-aa C-terminal domain that is proline-rich (14.1%) and contains an alternatively spliced domain, whose expression was previously shown to correlate with variable properties of tight junctions. dlg mutations result in loss of apical-basolateral epithelial cell polarity and in neoplastic growth. These results suggest a protein family specialized for signal transduction on the cytoplasmic surface of intercellular junctions. These results also provide biochemical evidence for similarity between invertebrate septate and vertebrate tight junctions. The C-terminal domain of ZO-1, and its alternatively spliced region, appears to confer variable properties unique to tight junctions.