title: Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane.
abstract: Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace.
authors.affiliation: Proteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona,  Consejo Superior de Investigaciones Cientificas, Barcelona Science Park, E-08028 Barcelona,  Spain.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Arolas
authors.forename: Claudia
authors.initials: C
authors.lastname: Broder
authors.forename: Tamara
authors.initials: T
authors.lastname: Jefferson
authors.forename: Tibisay
authors.initials: T
authors.lastname: Guevara
authors.forename: Erwin E
authors.initials: EE
authors.lastname: Sterchi
authors.forename: Wolfram
authors.initials: W
authors.lastname: Bode
authors.forename: Walter
authors.initials: W
authors.lastname: Stöcker
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker-Pauly
authors.forename: F Xavier
authors.initials: FX
authors.lastname: Gomis-Rüth
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D003461:Crystallography; D019281:Dimerization; D006801:Humans; D008666:Metalloendopeptidases / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D008666:Metalloendopeptidases; C053833:meprin A