title: Regulation of heterotypic claudin compatibility.
abstract: Tissue barrier function is directly mediated by tight junction transmembrane proteins known as claudins. Cells that form tight junctions typically express multiple claudin isoforms which suggests that heterotypic (head-to-head) binding between different claudin isoforms may play a role in regulating paracellular permeability. However, little is known about motifs that control heterotypic claudin compatibility. We found that although claudin-3 and claudin-4 were heteromerically compatible when expressed in the same cell, they did not heterotypically interact despite having extracellular loop (EL) domains that are highly conserved at the amino acid level. Claudin-1 and -5, which were heterotypically compatible with claudin-3, did not heterotypically bind to claudin-4. In contrast, claudin-4 chimeras containing either the first EL domain or the second EL domain of claudin-3 were able to heterotypically bind to claudin-1, claudin-3, and claudin-5. Moreover, a single point mutation in the first extracellular loop domain of claudin-3 to convert Asn(44) to the corresponding amino acid in claudin-4 (Thr) produced a claudin capable of heterotypic binding to claudin-4 while still retaining the ability to bind to claudin-1 and -5. Thus, control of heterotypic claudin-claudin interactions is sensitive to small changes in the EL domains.
authors: Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors: Brandy L
authors: BL
authors: Daugherty
authors: Christina
authors: C
authors: Ward
authors: Tekla
authors: T
authors: Smith
authors: Jeffrey D
authors: JD
authors: Ritzenthaler
authors: Michael
authors: M
authors: Koval
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D062445:Claudin-1; D062465:Claudin-3; D062506:Claudin-4; D062507:Claudin-5; D004847:Epithelial Cells / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid
chemical_list: C568108:CLDN1 protein, human; C568122:CLDN3 protein, human; C568157:CLDN4 protein, human; C107466:CLDN5 protein, human; D062445:Claudin-1; D062465:Claudin-3; D062506:Claudin-4; D062507:Claudin-5; D008565:Membrane Proteins; D020033:Protein Isoforms; D011994:Recombinant Proteins