Structure of the MUC5AC VWD3 assembly responsible for the formation of net-like mucin polymers

TL;DR

This study reveals the structure of MUC5AC mucin and how it forms net-like polymers in mucus, which could impact lung diseases.

Contribution

The paper provides the first cryoEM structures of MUC5AC D3 assembly and explains SNP effects on mucus organization.

Findings

The D3 assembly of MUC5AC forms covalent dimers in open and closed conformations.

The closed conformation allows tetramer formation via an arginine-rich loop in the TIL3 domain.

Common SNPs in the interaction surface affect intermolecular interactions and mucus organization.

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 D3 assembly of the human MUC5AC mucin and the structural single nucleotide polymorphisms (SNP) variants Arg996Gln and Arg1201Trp that affect intermolecular interactions. Our structures explain the MUC5AC N-terminal non-covalent oligomerization after secretion. The D3 assembly forms covalent dimers that can appear in two alternative conformations, open and closed, where the closed conformation dimers interact through an arginine-rich loop in the TIL3 domain to form tetramers. Our study provides a model to explain MUC5AC net-like structures and how the two SNPs will affect mucus organization, something that might affect lung and other diseases.

Mucins are highly glycosylated molecules that protect all mucosal surfaces of the body, including the lung. The respiratory disease associated MUC5AC mucin structure shows how it interacts with other MUC5AC to form net-like polymers.

The cryo-EM structure of the MUC5AC mucin shows how its linear form interacts to give net-like polymers.The interaction surface harbors common amino acid polymorphisms that increase interaction and affect mucus organization.

The cryo-EM structure of the MUC5AC mucin shows how its linear form interacts to give net-like polymers.

The interaction surface harbors common amino acid polymorphisms that increase interaction and affect mucus organization.

Mucins are highly glycosylated molecules that protect all mucosal surfaces of the body, including the lung. The respiratory disease associated MUC5AC mucin structure shows how it interacts with other MUC5AC to form net-like polymers.

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