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.