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

Using homology search, structure prediction, and structural characterizatio n methods we show that the C-terminal domains of (1) netrins, (2) complemen t 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 (TIM Ps). 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 T IMPs. it is not known at present what role the NTR modules play in these pr ocesses. 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 met alloprotease BMP1, it seems possible that interaction with metzincins could be a shared property of NTR modules and could be critical for the biologic al roles of the host proteins.