Metzincin

Bode W, Gomis-Ruth FX, Stocker W. Astacins, serralysins, snake venom and matrix metalloproteinases exhibit idential zinc-binding environments (HEXXHXXGXXH and Met-turn) and topologies and should be grouped into a common family, the metzincins. FEBS Lett 1993 331 134-140. 

The MMP enzyme family is part of the superfamily of metzincins. The metzincin superfamily is distinguished by a conserved zinc binding motif for the catalytic zinc and a Met-turn region [4]. The MMPs are unique in that they also contain a second structural zinc, however this zinc may be absent in the intact full-length enzyme [5]. The presence of one to four structural calcium ions has been detected in the MMPs that have been characterized to date. The importance of the zinc ions and at least one of the structural calcium ions to enzymatic activity has been proven [6]. 

Stocker W, Grams F, Baumann U, Gomis-Ruth F-X, McKay DB, Bode W. The metzincins topological and sequential relations between the astacins, adamalysins, serralysins, and matrixins (collagenases) define a superfamily of zinc peptidases. Protein Sci. 1995 4 823-840. 

The metzincins contain several sub-families. Astacins, bacterial serralysins, matrix metalloproteinases (MMPs), ADAMs (a disintegrating and metalloproteinase),... 

Fig. 2. Structure and active site of clostridial neurotoxins. The upper panel shows the structure of CNTs, and the segments that show significant homology between the different serotypes are in black (Minton, 1995). The highest homology is shown by a short segment corresponding to the amino acid residues 216-244 in TeTx. This segment contains the zinc-binding motif of metallo-proteinases (zincins) and it is dissimilar to the consensus sequence of the metzincin metallo-proteinase family (Jiang and Bond, 1992)...

Walasek, P. and Honek, J. F. (2005) Nonnatural amino acid incorporation into the methionine 214 position of the metzincin Pseudomonas aeruginosa alkaline protease. BMC Biochem., 6, 21. 

Stocker, W. and Bode, W. (1995) Structural features of a superfamily of zinc-endopeptidases the metzincins. Curr. Opin. Struct. Biol., 5(3), 383-390. 

Butler, G. S., Tam, E. M. and Overall, C. M. (2004) The canonical methionine 392 of matrix metalloproteinase 2 (gelatinase A) is not required for catalytic efficiency or structural integrity probing the role of the methionine-turn in the metzincin metalloprotease superfamily. J. Biol. Chem., 279(15), 15615-15620. 

Hege, T. and Baumann, U. (2001) The conserved methionine residue of the metzincins a site-directed mutagenesis study. J. Mol. Biol., 314(2), 181-186. 

The common structural elements in the metzincin superfamily are illustrated in Figure 12.7, for the catalytic domain of human MMP-8 (Phe79—Gly242) shown in standard orientation (PDB 1 JAN). The repetitive secondary structure elements (orange arrows for P-strands, pi—pV cyan ribbons for a-helices, aA—aC) and the four cations... 

All human metalloendoproteinases are metzincins, named for a downstream methionine residue involved in regulating catalysis by mediating a critical turn that brings an adjacent tyrosine or proline residue close to the catalytic zinc ion. Matrilysins (also called matrix metalloendoproteinases, MMPs) are the major class of metzincin endopeptidases involved in collagen and stromal degradation. The other two classes, adantalysins and... 

Exoproteinase Removes N-terminal amino acid Alanyl Aminopeptidase Metzincin... 

Endoproteinase Cuts a large polypeptide internally Matrilysins, adamalysins and astacins Metzincin... 

Fig. 8.1 Classification of metallopeptidases by zinc-binding motifs. The major amino acid motif in zincins has two histidine residues that coordinate with the metal ion and a glutamate residue (E) for catalysis. A third residue that coordinates with the metal may be glutamate, aspartate (D), or histidine. In metzincins, the third coordinating residue is histidine or aspartate (H/D), but the name is taken from the presence of a downstream invariant methionine residue (see Fig. 8.2 and text). The red type indicates enzymes or enzyme subfamilies encoded in the human genome (Slightly modified from Fig. 1A of F.X. Gomis-Ruth, Structural aspects of the metzincin clan of metal-loendopeptidases. Mol. Biotechnol. 24(2) 157-202, 2003)...

The metzincin catalytic domain consists of a flat surface within a small cleft within which peptide substrates bind and are hydrolyzed (Fig. 8.2a). In astacins, the catalytic domain is stable, but adamalysins require a calcium ion to stabilize the flat surface of the domain above the cleft. Matrilysins require two calcium ions and a second, noncatalytic zinc ion to stabilize this domain (Fig. 8.3). Table 8.3 reviews the roles of specific metal ions that participate in the various stages of collagen processing discussed in this chapter and Chap. 7. 

All human metzincins are secreted as proenzymes. Astacins and adamalysins are mostly activated by calcium-ion-dependent serine proteases pro-protein convertases) that meet up with their substrates in trans-Golgi and secretory vacuoles. These proenzymes are known as furin-like convertases because of their homology to a serine protease called furin and a bacterial endoprotease called subtilisin. The furin-like enzymes require calcium ions to maintain structural stability whereas other serine proteases, represented by trypsin and chymotrypsin, do not. The furin-like pro-protein convertases autocleave their own N-terminal domain propeptide (self-activate) during secretion and then convert the N-terminal domains of co-secreted metzincins. Activation cascades also occur among the... 

Fig.8.3 Architecture of astacins, adamalysin type-2, and matrix metalloproteases. Topology scheme of astacins, adamalysin type-2, and matrix metalloproteinases. The a-helices are shown as rods, 3-sheet strands as arrows, and unstructured regions as thin lines. Key amino acids in the catalytic, zinc-binding motif are shown (white in black ellipse). Distinguishing features of each structure are shown as lighter gray for amino acids (black letter), and as unlabeled, secondary-structure elements. In addition to the catalytic zinc ion in all three structures, the calcium ion in adamalysin type-2, and the two calcium ions and second zinc ion in the matrix metalloproteinases (Abbreviated from Fig. 3 in F.X. Gomis-Ruth, Structural aspects of the metzincin clan of metalloendopepti-dases. Mol. Biotechnol. 24(2) 157-202, 2003)...

---