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Article dans une revue

Assembly of the Respiratory Mucin MUC5B: A new model for a gel-forming mucin.

Abstract : Mucins are essential components in mucus gels that form protective barriers at all epithelial surfaces, but much remains unknown about their assembly, intragranular organization, and post-secretion unfurling to form mucus. MUC5B is a major polymeric mucin expressed by respiratory epithelia, and we investigated the molecular mechanisms involved during its assembly. Studies of intact polymeric MUC5B revealed a single high affinity calcium-binding site, distinct from multiple low affinity sites on each MUC5B monomer. Self-diffusion studies with intact MUC5B showed that calcium binding at the protein site catalyzed reversible cross-links between MUC5B chains to form networks. The site of cross-linking was identified in the MUC5B D3-domain as it was specifically blocked by D3 peptide antibodies. Biophysical analysis and single particle EM of recombinant MUC5B N terminus (D1D2D'D3; NT5B) and subdomains (D1, D1-D2, D2-D'-D3, and D3) generated structural models of monomers and disulfide-linked dimers and suggested that MUC5B multimerizes by disulfide linkage between D3-domains to form linear polymer chains. Moreover, these analyses revealed reversible homotypic interactions of NT5B at low pH and in high calcium, between disulfide-linked NT5B dimers, but not monomers. These results enable a model of MUC5B to be derived, which predicts mechanisms of mucin intracellular assembly and storage, which may be common to the other major gel-forming polymeric mucins.
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Soumis le : lundi 22 juillet 2019 - 14:48:34
Dernière modification le : mercredi 23 mars 2022 - 15:51:25


J. Biol. Chem.-2014-Ridley-164...
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Caroline Ridley, Nikos Kouvatsos, Bertrand D Raynal, Marj Howard, Richard F Collins, et al.. Assembly of the Respiratory Mucin MUC5B: A new model for a gel-forming mucin.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2014, 289 (23), pp.16409-20. ⟨10.1074/jbc.M114.566679⟩. ⟨hal-02178621⟩



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