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Article Dans Une Revue Journal of Biological Chemistry Année : 2014

Assembly of the Respiratory Mucin MUC5B


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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Dates et versions

hal-02178621 , version 1 (22-07-2019)





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, 2014, 289 (23), pp.16409-20. ⟨10.1074/jbc.M114.566679⟩. ⟨hal-02178621⟩
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