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Granule-stored MUC5B mucins are packed by the non-covalent formation of N-terminal head-to-head tetramers
Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
KTH, School of Technology and Health (STH). Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden.;Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden.
Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
Univ Gothenburg, Dept Med Biochem, Box 440, S-40530 Gothenburg, Sweden..
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 15, p. 5746-5754Article in journal (Refereed) Published
Abstract [en]

Most MUC5B mucin polymers in the upper airways of humans and pigs are produced by submucosal glands. MUC5B forms N-terminal covalent dimers that are further packed into larger assemblies because of low pH and high Ca2+ in the secretory granule of the mucin-producing cell. We purified the recombinant MUC5B N-terminal covalent dimer and used single-particle electron microscopy to study its structure under intracellular conditions. We found that, at intragranular pH, the dimeric MUC5B organized into head-to-head noncovalent tetramers where the von Willebrand D1-D2 domains hooked into each other. These N-terminal tetramers further formed long linear complexes from which, we suggest, the mucin domains and their C termini project radially outwards. Using conventional and video microscopy, we observed that, upon secretion into the submucosal gland ducts, a flow of bicarbonate-rich fluid passes the mucin-secreting cells. We suggest that this unfolds and pulls out the MUC5B assemblies into long linear threads. These further assemble into thicker mucin bundles in the glandular ducts before emerging at the gland duct opening. We conclude that the combination of intracellular packing of the MUC5B mucin and the submucosal gland morphology creates an efficient machine for producing linear mucin bundles.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018. Vol. 293, no 15, p. 5746-5754
National Category
Structural Biology
Identifiers
URN: urn:nbn:se:kth:diva-240245DOI: 10.1074/jbc.RA117.001014ISI: 000430044100033PubMedID: 29440393Scopus ID: 2-s2.0-85045345527OAI: oai:DiVA.org:kth-240245DiVA, id: diva2:1271237
Funder
Swedish Research CouncilSwedish Cancer SocietyKnut and Alice Wallenberg FoundationMagnus Bergvall FoundationSwedish Heart Lung Foundation
Note

QC 20181217

Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2018-12-17Bibliographically approved

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Nilsson, Harriet E.Köck, Philip J. B.Thornton, David J.
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