Structural mechanism of MUC5AC mucin net-like polymer formation and its SNP variability that affect risk of the lung diseases COPD and IPF

ABSTRACT Gel-forming mucins MUC5AC and MUC5B constitute the main structural component of the mucus in the respiratory system. Secreted mucins interact specifically with each other and other molecules giving mucus specific properties. We determined the cryoEM structures of the wild type MUC5AC-D3 assembly and the structural SNP variants R996Q and R1201W. Our structures explain the basis of MUC5AC N-terminal non-covalent oligomerization upon secretion. The MUC5AC-D3 assembly forms covalent dimers in two alternative conformations, open and closed. The closed conformation dimers interact through an arginine rich loop in the TIL3 domain forming tetramers. Moreover, we found a positive disease correlation between the SNP (R996Q, rs878913005), Chronic Obstructive Pulmonary Disease (COPD), and Idiopathic Pulmonary Fibrosis (IPF). The well-known MUC5B promotor SNP (rs35705950) association with IPF is much stronger when combined with the MUC5AC SNP. Our study provides a model to explain the formation of MUC5AC net-like structures and how both SNPs will affect mucus organization and increase risk of lung disease.