Intestinal Gel-forming Mucins Polymerize by Disulfide-Mediated Dimerization of the Conserved D3 and CysD1 Domains

Gel forming mucins comprise a family of heavily glycosylated proteins that self-assemble to form extracellular networks protecting epithelial surfaces. However, the mechanism by which these mucin networks form is only partially understood. Mucin 2 is the major component of the intestinal mucus layer where it simultaneously houses the microbiome and shields the epithelium from direct contact. The carboxy termini of two mucin 2 protomers covalently dimerize by disulfide bonding in the endoplasmic reticulum, but how these dimers further polymerize had been unclear. We recently determined the first high-resolution X-ray crystal structure of a mucin amino terminal domain and showed that it dimerizes via two inter-subunit disulfides. This finding rectified a decades-old misconception that this region trimerized to form branched networks. The strong conservation of amino acids at the amino-terminal dimer interface, including the intersubunit cysteines, supports the physiological relevance of the observed quaternary structure. Additionally, this new multimerization model for mucin 2 has wide reaching implications for other mucin proteins and the closely related blood protein von Willebrand factor. Current research in the lab focuses on further pushing our understanding of the supramolecular assembly of mucin proteins by examining non-covalent interactions important for assembly of protective networks.