The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions.
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.
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510.
E
E
Willott
M S
MS
Balda
A S
AS
Fanning
B
B
Jameson
C
C
Van Itallie
J M
JM
Anderson
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins; D004848:Epithelium / Q000502:physiology; D015723:Gene Library; D005804:Genes, Lethal; D016147:Genes, Tumor Suppressor; D051528:Guanylate Kinases; D006801:Humans; D007301:Insect Hormones / Q000235:genetics*; D007365:Intercellular Junctions / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011392:Proline; D051381:Rats; D015183:Restriction Mapping; D017386:Sequence Homology, Amino Acid; D013569:Synapses / Q000502:physiology; D025521:Tumor Suppressor Proteins; D062826:Zonula Occludens-1 Protein
D029721:Drosophila Proteins; D007301:Insect Hormones; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569044:Tjp1 protein, rat; D025521:Tumor Suppressor Proteins; D062826:Zonula Occludens-1 Protein; C070350:dlg1 protein, Drosophila; D004247:DNA; D011392:Proline; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases