Abstract
Metalloendopeptidases are present across all kingdoms of living organisms; they are ubiquitous and widely involved in metabolism regulation through their ability either to extensively degrade proteins or to selectively hydrolyze specific peptide bonds. They must be subjected to exquisite spatial and temporal control to prevent this vast potential from becoming destructive. These enzymes are mostly zinc-dependent and the majority of them, named zincins, possess a short consensus sequence, HEXXH, with the two histidines acting as ligands of the catalytic zinc and the glutamate as the general base. A subclass of the zincins is characterized by a C-terminally elongated motif, HEXXHXXGXXH/D, with an additional strictly conserved glycine and a third zinc-binding histidine or aspartate. Currently, representative three-dimensional structures of six different proteinase families bearing this motif show, despite low sequence similarity, comparable overall topology. This includes a substrate-binding crevice, which subdivides the enzyme moiety into an upper and a lower subdomain. A common five-stranded β-sheet and two α-helices are always found in the upper subdomain. The second of these helices encompasses the first half of the elongated consensus sequence and is therefore termed the active-site helix. Other shared characteristics are an invariant methionine-containing Met-turn beneath the catalytic metal and a further C-terminal helix in the lower subdomain. All these structural features identify the metzincin clan of metalloendopeptidases. This clan is reviewed from a structural point of view, based on the reported structures of representative members of the astacins, adamalysins, serralysins, matrixins, snapalysins, and leishmanolysins, and of inhibited forms, either by specific endogenous protein inhibitors or by zymogenic pro-domains. Moreover, newly available genomic sequences have unveiled novel putative metzincin families and new hypothetical members of existing ones.
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Abbreviations
- ABC:
-
ATP-binding cassette
- ADAM:
-
a disintegrin and metalloprotease
- ADAMTS:
-
ADAM with thrombospondin-like repeats
- BFT:
-
Bacteroides fragilis enterotoxin
- BMP:
-
bone morphogenetic protein
- CUB:
-
protein domain present in complement Clr/Cls, Uegf, and BMP-1
- ECM:
-
extracellular matrix
- EGF:
-
epidermal growth factor
- GLE:
-
gamete lytic enzyme
- GPI:
-
glycosyl phosphatidylinositol
- HIV:
-
human immunodeficiency virus
- HYBD:
-
hydrogenase-maturating endopeptidase B
- LSG2:
-
late somatic gene 2
- MATH:
-
meprin and TRAF homology domain
- MAM:
-
domain present in meprin, A-5 protein and tyrosine phosphatase μ
- MDC:
-
metalloprotease-like, disintegrin-like, and cysteine-rich proteins
- MEP:
-
metalloendopeptidase
- MMP:
-
matrix metalloproteinase alias vertebrate collagenase and matrixin
- MP:
-
metalloprotease
- MT-MMP:
-
membrane-type MMP
- ORF:
-
open-reading frame
- PAPP:
-
pregnancy-associated plasma protein
- PDB:
-
Protein Data Bank access code for three-dimensional structure coordinates
- RECK:
-
reversion-inducing cysteine-rich protein with Kazal motifs
- S1, S2, and P1, P2 :
-
denote protease activesite cleft and substrate subsites, respectively, N-terminally of the scissile peptide bond, S1′, S2′, and P1′, P2′, at the C-terminus of the scission, in accordance with ref. 27
- ScNP:
-
S. caespitosus neutral protease
- SVMP:
-
snake venom metalloproteinase
- TACE:
-
tumor-necrosis factor αconverting enzyme
- TGF:
-
transforming growth factor
- TIMP:
-
tissue inhibitor of metalloproteinases
- VMP:
-
Volvox metalloproteinase
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Gomis-Rüth, F.X. Structural aspects of the metzincin clan of metalloendopeptidases. Mol Biotechnol 24, 157–202 (2003). https://doi.org/10.1385/MB:24:2:157
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DOI: https://doi.org/10.1385/MB:24:2:157