The oligomerization of a family of four genetically clustered human gastrointestinal mucins |
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Authors: | van Klinken BJ; Einerhand AW; Buller HA; Dekker J |
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Institution: | Pediatric Gastroenterology and Nutrition, Academic Medical Center, Rm 68-260, University of Amsterdam, Amsterdam, The Netherlands. |
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Abstract: | Mucins are synthesized and secreted by many epithelia. They are complex
glycoproteins that offer cytoprotection. In their functional configuration,
mucins form oligomers by a biosynthetic process that is poorly understood.
A family of four human gastrointestinal mucin genes (MUC2, MUC5AC, MUC5B,
and MUC6) is clustered to chromosome 11p15.5. To study oligomerization of
these related mucins, we performed metabolic labeling experiments with
35S]amino acids in LS174T cells, and isolated mucin precursors by specific
immunoprecipitations that were analyzed on SDS-PAGE. Each of the precursors
of MUC2, MUC5AC, MUC5B, and MUC6 formed a single species of
disulfide-linked homo-oligomer within 1 h after pulse labeling. Based on
apparent molecular masses, these oligomeric precursors were most likely
dimers. Inhibition of vesicular RER-to-Golgi transport, with brefeldin A
and CCCP, did not affect the dimerization of MUC2 precursors, localizing
dimerization to the RER. O-Glycosylation of MUC2 followed dimerization.
Inhibition of N- glycosylation by tunicamycin retarded, but did not
inhibit, dimerization, indicating that N-glycans play a role in efficient
dimerization of MUC2 precursors. Based on sequence homology, the ability of
MUC2, MUC5AC, MUC5B and MUC6 to dimerize most likely resides in their
C-terminal domains. Thus, the RER-localized dimerization of secretory
mucins likely proceeds by similar mechanisms, which is an essential step in
the formation of the human gastrointestinal mucus- gels.
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