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Human tight junction protein 3 (zona occludens 3), kinase domain

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PDB Code 3KFV Target Class Non-protein Kinase Target TJP3 Alias n/a Disease Area/Function Date Deposited Oct 28 2009 Authors Tong Y, Nedyalkova L, Tempel W, Zhong N, Guan X, Arrowsmith CH, Edwards AM, Bountra C, Weigelt J, Bochkarev A, Park HW

About this structure

Tight junction (TJ) is composed of a branching network of sealing strands which links adjacent epithelial or endothelial cells and plays a barrier role by regulating the passage of ions and molecules through the paracellular pathway[1,2]. TJP3/ZO-3 (tight junction protein 3 or zonula occludens 3) is a TJ cytoplasmic plaque protein. TJP3 consists of three PDZ domains (PDZ1-PDZ3), one SH3 domain, and one guanylate kinase (GK) domain, and belongs to the membrane-associated guanylate kinase (MAGUK) family. The PDZ2 domain of TJP3 binding to that of TJP1 to form a stable complex[3]. The PDZ1 domain of TJP3 binds to a transmembrane TJ protein claudin, localizing it at the TJ region to carry out function for cell-cell adhesion[4]. The GK domain of TJP3 is homologous to the enzyme that catalyzes the conversion of GMP to GDP at the expense of ATP. But the TJP proteins are predicted to bind neither GMP nor ATP and thus are enzymatically inactive[5].

Here, we solved the crystal structure of the apo-form of a fragment of TJP3 containing the SH3 and GK domains. The SH3 domain adopts a typical α/β fold, while the GK domain shows an incomplete kinase fold, where the N-lobe is missing, thus collapsing the cleft between the N- and C-lobes. Since the cleft forms the nucleotide binding site (i.e.,g GMP and ATP) in authentic kinases, the TJP3 structure explains that the enzymatic inactivation of TJP3 is due to GMP and ATP being unable to bind to the collapsed cleft.

References

  1. J.M. Anderson and M. Cereijido (2001) Introduction: evolution of ideas on the tight junction, CRC Press, Boca Raton pp. 1–18.
  2. Cereijido M, González-Mariscal L, Contreras RG, Gallardo JM, García-Villegas R, Valdés J (1993) The making of a tight junction. J Cell Sci 17:127–132
  3. Wittchen ES, Haskins J, Stevenson BR (1999) Protein interactions at the tight junction: actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. J Biol Chem 274:35179–35185
  4. Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S (1999) Direct binding of three tight junctionassociated MAGUKs, ZO-1, ZO-2 and ZO-3, with the COOH termini of claudins. J Cell Biol 147:1351–1363
  5. González-Mariscal L, Betanzos A, Avila-Flores A (2000) MAGUK proteins: structure and role in the tight junction. Semin Cell Dev Biol 11(4):315-24.