title: Generation of ligand-receptor alliances by "SEA" module-mediated cleavage of membrane-associated mucin proteins.
abstract: A mechanism is described whereby one and the same gene can encode both a receptor protein as well as its specific ligand. Generation of this receptor-ligand partnership is effected by proteolytic cleavage within a specific module located in a membrane resident protein. It is postulated here that the "SEA" module, found in a number of heavily O-linked glycosylated membrane-associated proteins, serves as a site for proteolytic cleavage. The subunits generated by proteolytic cleavage of the SEA module reassociate, and can subsequently elicit a signaling cascade. We hypothesize that all membrane resident proteins containing such a "SEA" module will undergo cleavage, thereby generating a receptor-ligand alliance. This requires that the protein subunits resulting from the proteolytic cleavage reassociate with each other in a highly specific fashion. The same SEA module that serves as the site for proteolytic cleavage, probably also contains the binding sites for reassociation of the resultant two subunits. More than one type of module can function as a site for proteolytic cleavage; this can occur not only in one-pass membrane proteins but also in 7-transmembrane proteins and other membrane-associated proteins. The proposal presented here is likely to have significant practical consequences. It could well lead to the rational design and identification of molecules that, by binding to one of the cleaved partners, will act either as agonists or antagonists, alter signal transduction and, hence, cellular behavior.
authors.affiliation: Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel. danielhw@post.tau.ac.il
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Wreschner
authors.forename: Michael A
authors.initials: MA
authors.lastname: McGuckin
authors.forename: Stefanie J
authors.initials: SJ
authors.lastname: Williams
authors.forename: Amos
authors.initials: A
authors.lastname: Baruch
authors.forename: Merav
authors.initials: M
authors.lastname: Yoeli
authors.forename: Ravit
authors.initials: R
authors.lastname: Ziv
authors.forename: Liron
authors.initials: L
authors.lastname: Okun
authors.forename: Joseph
authors.initials: J
authors.lastname: Zaretsky
authors.forename: Nechama
authors.initials: N
authors.lastname: Smorodinsky
authors.forename: Iafa
authors.initials: I
authors.lastname: Keydar
authors.forename: Pavlos
authors.initials: P
authors.lastname: Neophytou
authors.forename: Martin
authors.initials: M
authors.lastname: Stacey
authors.forename: His-Hsien
authors.initials: HH
authors.lastname: Lin
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019281:Dimerization; D010450:Endopeptidases / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017385:Sequence Homology
chemical_list: D029742:Caenorhabditis elegans Proteins; D008024:Ligands; D018396:Mucin-1; D010450:Endopeptidases