MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins

• 成果类型: Article
• 署名作者: Haberman, Meital; Kamyshinsky, Roman; Reznik, Nava; Yeshaya, Noa; Khmelnitsky, Lev; Plender, Elizabeth G.; Eichler, Evan E.; Fass, Deborah
• 署名单位: Weizmann Institute of Science; Weizmann Institute of Science; University of Washington; University of Washington Seattle; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; Howard Hughes Medical Institute; University of Washington; University of Washington Seattle
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11505
• DOI: 10.1073/pnas.2419717122
• 发表日期: 2025-03-11
• 关键词: von-willebrand-factor; validation; MODEL

摘要

Secreted mucins are multimegadalton glycoprotein polymers that share the function of protecting mucosal tissues but diversified for activities in different organs of the body. Structural studies of secreted mucins are complicated by the enormous sizes, flexibility, and complex supramolecular assembly modes of these glycoproteins. The two major respiratory mucins are MUC5AC and MUC5B. Here, we present structures of a large amino-terminal segment of MUC5AC in the form of helical filaments. These filaments differ from filamentous and tubular structures observed previously for the intestinal mucin MUC2 and the partial mucin homolog VWF. Nevertheless, the MUC5AC helical filaments support the proposed mechanism, based on MUC2 and VWF, for how noncovalent interactions between mucin monomers guide disulfide crosslinking to form polymers. The high-resolution MUC5AC structures show how local and limited changes in amino acid sequence can profoundly affect higher-order assembly while preserving the overall folds and polymerization activity of mucin glycoproteins. Differences in supramolecular assembly are likely to be functionally significant considering the divergence of mechanical properties and physiological requirements between respiratory and intestinal mucins. Determining the high-resolution structures of respiratory mucins provides a foundation for understanding the mechanisms by which they clean and protect the lungs. Moreover, the MUC5AC structure enables visualization of the sites of human amino acid sequence variation and disease-associated mutations.