title: Autoproteolysis coupled to protein folding in the SEA domain of the membrane-bound MUC1 mucin.
abstract: The single cell layer of the lungs and the gastrointestinal tract is protected by the mucus formed by large glycoproteins called mucins. Transmembrane mucins typically contain 110-residue SEA domains located next to the membrane. These domains undergo post-translational cleavage between glycine and serine in a characteristic GSVVV sequence, but the two peptides remain tightly associated. We show that the SEA domain of the human MUC1 transmembrane mucin undergoes a novel type of autoproteolysis, which is catalyzed by conformational stress and the conserved serine hydroxyl. We propose that self-cleaving SEA domains have evolved to dissociate as a result of mechanical rather than chemical stress at the apical cell membrane and that this protects epithelial cells from rupture. We further suggest that the cell can register mechanical shear at the mucosal surface if the dissociation is signaled via loss of a SEA-binding protein.
authors.affiliation: Department of Medical Biochemistry, Göteborg University, Box 440, SE-405 30 Göteborg, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Macao
authors.forename: Denny G A
authors.initials: DG
authors.lastname: Johansson
authors.forename: Gunnar C
authors.initials: GC
authors.lastname: Hansson
authors.forename: Torleif
authors.initials: T
authors.lastname: Härd
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013696:Temperature
chemical_list: D018396:Mucin-1