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Formation of tight junction: determinants of homophilic interaction between classic claudins

Jörg Piontek^*,1, Lars Winkler^*,1, Hartwig Wolburg, Sebastian L. Müller^*, Nikolaj Zuleger^*,2, Christian Piehl^*, Burkhard Wiesner^*, Gerd Krause^*,3 and Ingolf E. Blasig^*

^* Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany; and

Institute of Pathology, University of Tübingen, Tübingen, Germany

³ Correspondence: Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125 Berlin, Germany. E-mail: gkrause{at}fmp-berlin.de

Claudins are the critical transmembrane proteins in tight junctions. Claudin-5, for instance, prevents paracellular permeation of small molecules. However, the molecular interaction mechanism is unknown. Hence, the claudin-claudin interaction and tight junction strand formation were investigated using systematic single mutations. Claudin-5 mutants transfected into tight junction-free cells demonstrated that the extracellular loop 2 is involved in strand formation via trans-interaction, but not via polymerization, along the plasma membrane of one cell. Three phenotypes were obtained: the tight junction type (wild-type-like trans- and cis-interaction; the disjunction type (blocked trans-interaction); the intracellular type (disturbed folding). Combining site-directed mutagenesis, live-cell imaging-, electron microscopy-, and molecular modeling data led to an antiparallel homodimer homology model of the loop. These data for the first time explain how two claudins hold onto each other and constrict the paracellular space. The intermolecular interface includes aromatic (F147, Y148, Y158) and hydrophilic (Q156, E159) residues. The aromatic residues form a strong binding core between two loops from opposing cells. Since nearly all these residues are conserved in most claudins, our findings are of general relevance for all classical claudins. On the basis of the data we have established a novel molecular concept for tight junction formation.—Piontek, J., Winkler, L., Wolburg, H., Müller, S. L., Zuleger, N., Piehl, C., Wiesner, B., Krause, G., Blasig, I. E. Formation of tight junction: determinants of homophilic interaction between classic claudins.

Key Words: transmembrane protein • protein-protein interaction • cell-cell contacts • freeze-fracturing • FRET

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