From Monomer to Mesh: The Biochemical Maturation of Gel-Forming Mucin Glycoproteins

Abstract

Secreted mucin glycoproteins, which form the scaffolds of the mucus hydrogels coating tissue epithelia, are among the most complex molecules in nature. Mucin protein backbones are typically more than 5000 amino acids in length, become stapled into domain folds by over 100 disulfide bonds, and contain thousands of potential sites for O-glycosylation. The glycans added to these sites vary in chemical composition, length, and degree of branching, producing mucins with diverse biochemical and biophysical properties. In addition to this chemical complexity, structural heterogeneity arises via hinges between domains, long segments of natively disordered polypeptide, and intrinsic glycan flexibility. Though mucin backbone amino acid sequences are encoded in the genome, the ultimate properties of mucins depend heavily on glycosylation, which is shaped dynamically by the sets of glycosyltransferases expressed in individual mucus-producing cells. The substantial energy and intracellular organization required to produce mucin glycoproteins pays off in their crucial and versatile biological functions, ranging from cleaning tissue surfaces to lubrication to microbiome management. Mucins are of particular interest in human health due to their roles in protecting the respiratory and gastrointestinal tracts and their dysfunction in various diseases. Studying the elaborate maturation process during mucin biosynthesis and polymerization, decoration with glycans, and formation of interpolymer interactions may help identify vulnerabilities that can be overcome nutritionally or medically. Understanding the principles of mucin construction will provide the framework for strengthening mucus hydrogels both physically and functionally.