Assembly of Tight Junction Strands: Claudin-10b and Claudin-3 Form Homo-Tetrameric Building Blocks that Polymerise in a Channel-Independent Manner

Journal of Molecular Biology
Caroline HempelJörg Piontek

Abstract

Tight junctions regulate paracellular permeability size and charge selectively. Models have been proposed for the molecular architecture of tight junction strands and paracellular channels. However, they are not fully consistent with experimental and structural data. Here, we analysed the architecture of claudin-based tight junction strands and channels by cellular reconstitution of strands, structure-guided mutagenesis, in silico protein docking and oligomer modelling. Prototypic channel- (Cldn10b) and barrier-forming (Cldn3) claudins were analysed. Förster resonance energy transfer (FRET) assays indicated multistep claudin polymerisation, starting with cis-oligomerization specific to the claudin subtype, followed by trans-interaction-triggered cis-polymerisation. Alternative protomer interfaces were modelled in silico and tested by cysteine-mediated crosslinking, confocal- and freeze fracture EM-based analysis of strand formation. The analysed claudin mutants included also mutations causing the HELIX syndrome. The results indicated that protomers in Cldn10b and Cldn3 strands form similar antiparallel double rows, as has been suggested for Cldn15. Mutually stabilising -hydrophilic and hydrophobic - cis- and trans-interfaces we...Continue Reading

Citations

Jan 3, 2021·Pflügers Archiv : European journal of physiology·Carolin SchilppOliver H Wittekindt
Mar 22, 2021·The Journal of Biological Chemistry·Fei LiRobert M Stroud
Apr 21, 2021·Proceedings of the National Academy of Sciences of the United States of America·Alex J VecchioRobert M Stroud
Jul 25, 2021·International Journal of Molecular Sciences·Ashley MonacoKurt Amsler
May 23, 2020·Drug Discovery Today·Yosuke HashimotoMasuo Kondoh

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