The Structure and Assembly of Secreted Mucins

Abstract

porcine submaxillary mucin bovine submaxillary mucin canine tracheobronchial mucin frog integumentary mucin mouse submandibular mucin porcine gastric mucin rat submandibular mucin human von Willebrand factor Mucins are major glycoprotein components of the mucous that coats the surfaces of cells lining the respiratory, digestive, and urogenital tracts, and in some amphibia, the skin. They function to protect epithelial cells from infection, dehydration, and physical or chemical injury, as well as to aid the passage of materials through a tract. Individual organisms make several structurally different mucins, and a given mucin may be found in more than one organ (see Supplemental Material). Members of the mucin family can differ considerably in size. Some are small, containing a few hundred amino acid residues, whereas others contain several thousands of residues and are among the largest known proteins. Irrespective of size, all mucin polypeptide chains have domains rich in threonine and/or serine whose hydroxyl groups are in O-glycosidic linkage with oligosaccharides. Moreover, these domains are composed of tandemly repeated sequences that vary in number, length, and amino acid sequence from one mucin to another (1Gendler S.J. Spicer A.P. Annu. Rev. Physiol. 1995; 37: 607-634Crossref Scopus (854) Google Scholar). The carbohydrate content of a mucin may account for up to 90% of its weight. There are two types of mucins, membrane-bound and secreted. Of the human mucins, two are membrane-bound (MUC1 and MUC4) (2Gendler S.J. Lancaster C.A. Taylor-Papadimitriu J. Duhig T. Peat N. Burchell J. Pemberton L. Lalani E.N. Wilson D. J. Biol. Chem. 1990; 265: 15286-15293Abstract Full Text PDF PubMed Google Scholar, 3Moniaux N. Nollet S. Porchet N. Degand P. Laine A. Aubert J.-P. Biochem. J. 1999; 338: 325-333Crossref PubMed Scopus (219) Google Scholar) and four are secreted (MUC2, MUC5AC, MUC5B, and MUC7) (4Gum J.R. Hicks J.W. Toribara N.W. Siddiki B. Kim Y.S. J. Biol. Chem. 1994; 269: 2440-2446Abstract Full Text PDF PubMed Google Scholar, 5Li D. Gallup M. Fan N. Szymkowski D.E. Basbaum C.B. J. Biol. Chem. 1998; 273: 6812-6820Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 6Desseyn J.L. Aubert J.P. van Seuningen I. Porchet N. Laine A. J. Biol. Chem. 1997; 272: 16873-16883Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 7Bobek L.A. Tsa H. Biesbrock A.R. Levine M.J. J. Biol. Chem. 1993; 268: 20563-20569Abstract Full Text PDF PubMed Google Scholar). The three other mucins (MUC3, MUC6, and MUC8) (8Gum J.R. Ho J.J.L. Pratt W.S. Hicks J.W. Hill A.S. Vinall L.E. Roberton A.M. Swallow D.M. Kim Y.S. J. Biol. Chem. 1992; 267: 26678-26686Abstract Full Text PDF Google Scholar, 9Toribara N.W. Ho S.B. Gum E. Gum J.R. Lau P. Kim Y.S. J. Biol. Chem. 1997; 272: 16398-16403Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 10Shankar V. Pichan P. Eddy Jr., R.L. Tonk V. Nowak N. Sait S.N. Shows T.B. Schultz R.E. Gotway G. Elkins R.C. Gilmore M.S. Sachdev G.P. Am. J. Respir. Cell Mol. Biol. 1997; 16: 232-241Crossref PubMed Scopus (128) Google Scholar, 11Pigny P. Guyonnet-Duperat V. Hill A.S. Pratt W.S. Galiegue-Zouitina S. Vinall L. Collyn D'Hooge M. Laine A. Van-Seuningen I. Degand P. Gum J.R. Kim Y.S. Swallow D.M. Aubert J.-P. Porchet N. Genomics. 1996; 38: 340-352Crossref PubMed Scopus (187) Google Scholar) cannot be classified. Each human mucin has a counterpart in other animals. Thus, porcine submaxillary mucin (PSM)1 (12Eckhardt A.E. Timpte C.S. DeLuca A.W. Hill R.L. J. Biol. Chem. 1997; 272: 33204-33210Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar), one of the most thoroughly characterized mucins, has a tissue distribution and structure similar to MUC5B. An increasing number of proteins that are not mucins also contain highly O-glycosylated domains called “mucin-like domains.” The functions of mucins are dependent on their ability to form viscous solutions or gels. Although the highly glycosylated domains of mucins are devoid of secondary structures, they are long extended structures that are much less flexible than unglycosylated random coils. The oligosaccharides contribute to this stiffness in two ways, by limiting the rotation around peptide bonds and by charge repulsion among the neighboring, negatively charged oligosaccharide groups (13Jentoft N. Trends Biochem. Sci. 1991; 15: 291-294Abstract Full Text PDF Scopus (621) Google Scholar). Such long, extended molecules have a much greater solution volume than native or denatured proteins with little or no carbohydrate and endow aqueous mucin solutions with a high viscosity. Mucins protect against infection by microorganisms that bind cell surface carbohydrates, and mucin genes appear to be up-regulated by substances derived from bacteria, e.g. lipopolysaccharides (14Dohrman A. Miyata S. Gallup M. Li J.D. Chapelin C. Coste A. Escudier E. Nadel J. Basbaum C. Biochim. Biophys. Acta. 1998; 1406: 251-259Crossr