MUC5AC filaments illuminate the structural diversification of respiratory and intestinal mucins.

Summary

High-resolution structures of the MUC5AC amino-terminal region reveal helical filaments distinct from MUC2 and VWF assemblies, explaining how sequence variation directs higher-order polymer formation. These findings clarify conserved polymerization mechanisms and map disease-relevant variation sites in respiratory mucins.

Key Findings

• Resolved helical filament structures of a large N-terminal segment of MUC5AC.
• MUC5AC filaments differ from MUC2 and VWF assemblies yet support conserved noncovalent-guided disulfide polymerization.
• Minor local sequence differences markedly alter higher-order assembly without disrupting domain folds.
• Structural maps enable visualization of human variation and disease-associated mutations in MUC5AC.

Clinical Implications

While preclinical, structural insights may guide rational design of mucolytics or polymer-modifying therapies and inform interpretation of human variants affecting mucus properties.

Limitations

• Structures pertain to an amino-terminal segment rather than full-length, fully glycosylated mucins.
• Functional validation in vivo and direct links to disease phenotypes were not established.

Future Directions

Extend structural analysis to full-length mucins and mixed assemblies (MUC5AC/MUC5B), integrate with rheology and in vivo models, and test small molecules or peptides that modulate assembly.