Regulation of heterotypic claudin compatibility.
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.
Daugherty
Brandy L
BL
Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Ward
Christina
C
Smith
Tekla
T
Ritzenthaler
Jeffrey D
JD
Koval
Michael
M
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
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