Role of the netrin-like domain of procollagen C-proteinase enhancer-1 in the control of metalloproteinase activity

Mourad Bekhouche, Daniel Kronenberg, Sandrine Vadon-Le Goff, Cécile Bijakowski, Ngee Han Lim, Bernard Font, Efrat Kessler, Alain Colige, Hideaki Nagase, Gillian Murphy, David J.S. Hulmes, Catherine Moali

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

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.

Original languageEnglish
Pages (from-to)15950-15959
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number21
DOIs
StatePublished - 21 May 2010

Funding

FundersFunder number
National Institute of Arthritis and Musculoskeletal and Skin DiseasesR01AR040994
National Institute of Arthritis and Musculoskeletal and Skin Diseases

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