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Structural aspects of the metzincin clan of metalloendopeptidases

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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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  1. Institut de Biologia Molecular de Barcelona, C.I.D.—C.S.I.C., C/ Jordi Girona, 18-26, 08034, Barcelona, Spain

    F. Xavier Gomis-Rüth

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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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