Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity.
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.
Bekhouche
Mourad
M
From the Institut de Biologie et Chimie des Protéines, CNRS/Université de Lyon UMR 5086, IFR128, 69367 Lyon, France.
Kronenberg
Daniel
D
Vadon-Le Goff
Sandrine
S
Bijakowski
Cécile
C
Lim
Ngee Han
NH
Font
Bernard
B
Kessler
Efrat
E
Colige
Alain
A
Nagase
Hideaki
H
Murphy
Gillian
G
Hulmes
David J S
DJ
Moali
Catherine
C
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*
D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C491555:PCOLCE protein, human; D011347:Procollagen; D019714:Tissue Inhibitor of Metalloproteinases; D055394:Tolloid-Like Metalloproteinases; D051722:ADAM Proteins