The NTR module: domains of netrins, secreted frizzled related proteins, and type I procollagen C-proteinase enhancer protein are homologous with tissue inhibitors of metalloproteases

Protein Sci. 1999 Aug;8(8):1636-42. doi: 10.1110/ps.8.8.1636.


Using homology search, structure prediction, and structural characterization methods we show that the C-terminal domains of (1) netrins, (2) complement proteins C3, C4, C5, (3) secreted frizzled-related proteins, and (4) type I procollagen C-proteinase enhancer proteins (PCOLCEs) are homologous with the N-terminal domains of (5) tissue inhibitors of metalloproteinases (TIMPs). The proteins harboring this netrin module (NTR module) fulfill diverse biological roles ranging from axon guidance, regulation of Wnt signaling, to the control of the activity of metalloproteases. With the exception of TIMPs, it is not known at present what role the NTR modules play in these processes. In view of the fact that the NTR modules of TIMPs are involved in the inhibition of matrixin-type metalloproteases and that the NTR module of PCOLCEs is involved in the control of the activity of the astacin-type metalloprotease BMP1, it seems possible that interaction with metzincins could be a shared property of NTR modules and could be critical for the biological roles of the host proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Circular Dichroism
  • DNA Primers
  • Extracellular Matrix Proteins
  • Eye Proteins / chemistry*
  • Glycoproteins / chemistry*
  • Humans
  • Membrane Proteins*
  • Molecular Sequence Data
  • Nerve Growth Factors / chemistry*
  • Protein Structure, Secondary
  • Proteins*
  • Recombinant Proteins / chemistry
  • Sequence Homology, Amino Acid
  • Spectrophotometry, Ultraviolet
  • Tissue Inhibitor of Metalloproteinases / chemistry*


  • DNA Primers
  • Extracellular Matrix Proteins
  • Eye Proteins
  • Glycoproteins
  • Membrane Proteins
  • Nerve Growth Factors
  • PCOLCE protein, human
  • Proteins
  • Recombinant Proteins
  • SFRP2 protein, human
  • Sfrp2 protein, mouse
  • Tissue Inhibitor of Metalloproteinases