title: Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity.
abstract: The netrin-like (NTR) domain is a feature of several extracellular proteins, most notably the N-terminal domain of tissue inhibitors of metalloproteinases (TIMPs), where it functions as a strong inhibitor of matrix metalloproteinases and some other members of the metzincin superfamily. The presence of a C-terminal NTR domain in procollagen C-proteinase enhancers (PCPEs), proteins that stimulate the activity of astacin-like tolloid proteinases, raises the possibility that this might also have inhibitory activity. Here we show that both long and short forms of the PCPE-1 NTR domain, the latter beginning at the N-terminal cysteine known to be critical for TIMP activity, show no inhibition, at micromolar concentrations, of several members of the metzincin superfamily, including matrix metalloproteinase-2, bone morphogenetic protein-1 (a tolloid proteinase), and different ADAMTS (a disintegrin and a metalloproteinase with thrombospondin motifs) proteinases from the adamalysin family. In contrast, we report that the NTR domain within PCPE-1 leads to superstimulation of bone morphogenetic protein-1 activity in the presence of heparin and heparan sulfate. These observations point to a new mechanism whereby binding to cell surface-associated or extracellular heparin-like sulfated glycosaminoglycans might provide a means to accelerate procollagen processing in specific cellular and extracellular microenvironments.
authors.affiliation: From the Institut de Biologie et Chimie des Protéines, CNRS/Université de Lyon UMR 5086, IFR128, 69367 Lyon, France.
authors.forename: Mourad
authors.initials: M
authors.lastname: Bekhouche
authors.forename: Daniel
authors.initials: D
authors.lastname: Kronenberg
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vadon-Le Goff
authors.forename: Cécile
authors.initials: C
authors.lastname: Bijakowski
authors.forename: Ngee Han
authors.initials: NH
authors.lastname: Lim
authors.forename: Bernard
authors.initials: B
authors.lastname: Font
authors.forename: Efrat
authors.initials: E
authors.lastname: Kessler
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
authors.forename: David J S
authors.initials: DJ
authors.lastname: Hulmes
authors.forename: Catherine
authors.initials: C
authors.lastname: Moali
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011347:Procollagen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019714:Tissue Inhibitor of Metalloproteinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055394:Tolloid-Like Metalloproteinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C491555:PCOLCE protein, human; D011347:Procollagen; D019714:Tissue Inhibitor of Metalloproteinases; D055394:Tolloid-Like Metalloproteinases; D051722:ADAM Proteins