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J Biol Chem. 2018 Apr 13;293(15):5746-5754. doi: 10.1074/jbc.RA117.001014. Epub 2018 Feb 13.

Granule-stored MUC5B mucins are packed by the non-covalent formation of N-terminal head-to-head tetramers.

Author information

1
From the Department of Medical Biochemistry, University of Gothenburg, 40530 Gothenburg, Sweden.
2
the Department of Biosciences and Nutrition, Karolinska Institutet, 14157 Huddinge, Sweden.
3
the School of Technology and Health, KTH Royal Institute of Technology, 14157 Huddinge, Sweden.
4
the Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester M139PT, United Kingdom.
5
the Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig Maximilians University Munich, Hackerstrasse 27, 85764 Oberschleissheim, Germany, and.
6
the Cystic Fibrosis Research Laboratory, Stanford University, Stanford, California 94305.
7
From the Department of Medical Biochemistry, University of Gothenburg, 40530 Gothenburg, Sweden, gunnar.hansson@medkem.gu.se.

Abstract

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.

KEYWORDS:

EM; lung; mucin; mucin bundle; mucus; regulated secretory pathway; secretion; submucosal gland

PMID:
29440393
PMCID:
PMC5900763
DOI:
10.1074/jbc.RA117.001014
[Indexed for MEDLINE]
Free PMC Article

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