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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.

Original publication

DOI

10.1074/jbc.m109.086447

Type

Journal article

Journal

The Journal of biological chemistry

Publication Date

05/2010

Volume

285

Pages

15950 - 15959

Addresses

From the Institut de Biologie et Chimie des Protéines, CNRS/Université de Lyon UMR 5086, IFR128, 69367 Lyon, France.

Keywords

Cell Line, Humans, Glycoproteins, Procollagen, Extracellular Matrix Proteins, Tissue Inhibitor of Metalloproteinases, Protein Structure, Tertiary, ADAM Proteins, Tolloid-Like Metalloproteinases