PROSITE documentation PDOC00129
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{PDOC00129}
{PS00142; ZINC_PROTEASE}
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* Neutral zinc metallopeptidases, zinc-binding region signature *
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The majority of zinc-dependent metallopeptidases (with the notable exception
of the carboxypeptidases) share a common pattern of primary structure [1,2,3]
in the part of their sequence involved in the binding of zinc, and can be
grouped together as a superfamily,known as the metzincins, on the basis of
this sequence similarity. They can be classified into a number of distinct
families [4,E1] which are listed below along with the proteases which are
currently known to belong to these families.
Family M1
- Bacterial aminopeptidase N (EC 3.4.11.2) (gene pepN).
- Mammalian aminopeptidase N (EC 3.4.11.2).
- Mammalian glutamyl aminopeptidase (EC 3.4.11.7) (aminopeptidase A). It may
play a role in regulating growth and differentiation of early B-lineage
cells.
- Yeast aminopeptidase yscII (gene APE2).
- Yeast alanine/arginine aminopeptidase (gene AAP1).
- Yeast hypothetical protein YIL137c.
- Leukotriene A-4 hydrolase (EC 3.3.2.6). This enzyme is responsible for the
hydrolysis of an epoxide moiety of LTA-4 to form LTB-4; it has been shown
that it binds zinc and is capable of peptidase activity.
Family M2
- Angiotensin-converting enzyme (EC 3.4.15.1) (dipeptidyl carboxypeptidase I)
(ACE) the enzyme responsible for hydrolyzing angiotensin I to angiotensin
II. There are two forms of ACE: a testis-specific isozyme and a somatic
isozyme which has two active centers.
Family M3
- Thimet oligopeptidase (EC 3.4.24.15), a mammalian enzyme involved in the
cytoplasmic degradation of small peptides.
- Neurolysin (EC 3.4.24.16) (also known as mitochondrial oligopeptidase M or
microsomal endopeptidase).
- Mitochondrial intermediate peptidase precursor (EC 3.4.24.59) (MIP). It is
involved the second stage of processing of some proteins imported in the
mitochondrion.
- Yeast saccharolysin (EC 3.4.24.37) (proteinase yscD).
- Escherichia coli and related bacteria dipeptidyl carboxypeptidase
(EC 3.4.15.5) (gene dcp).
- Escherichia coli and related bacteria oligopeptidase A (EC 3.4.24.70) (gene
opdA or prlC).
- Yeast hypothetical protein YKL134c.
Family M4
- Thermostable thermolysins (EC 3.4.24.27), and related thermolabile neutral
proteases (bacillolysins) (EC 3.4.24.28) from various species of Bacillus.
- Pseudolysin (EC 3.4.24.26) from Pseudomonas aeruginosa (gene lasB).
- Extracellular elastase from Staphylococcus epidermidis.
- Extracellular protease prt1 from Erwinia carotovora.
- Extracellular minor protease smp from Serratia marcescens.
- Vibriolysin (EC 3.4.24.25) from various species of Vibrio.
- Protease prtA from Listeria monocytogenes.
- Extracellular proteinase proA from Legionella pneumophila.
Family M5
- Mycolysin (EC 3.4.24.31) from Streptomyces cacaoi.
Family M6
- Immune inhibitor A from Bacillus thuringiensis (gene ina). Ina degrades two
classes of insect antibacterial proteins, attacins and cecropins.
Family M7
- Streptomyces extracellular small neutral proteases
Family M8
- Leishmanolysin (EC 3.4.24.36) (surface glycoprotein gp63), a cell surface
protease from various species of Leishmania.
Family M9
- Microbial collagenase (EC 3.4.24.3) from Clostridium perfringens and Vibrio
alginolyticus.
Family M10A
- Serralysin (EC 3.4.24.40), an extracellular metalloprotease from Serratia.
- Alkaline metalloproteinase from Pseudomonas aeruginosa (gene aprA).
- Secreted proteases A, B, C and G from Erwinia chrysanthemi.
- Yeast hypothetical protein YIL108w.
Family M10B
- Mammalian extracellular matrix metalloproteinases (known as matrixins) [5]:
MMP-1 (EC 3.4.24.7) (interstitial collagenase), MMP-2 (EC 3.4.24.24) (72 Kd
gelatinase), MMP-9 (EC 3.4.24.35) (92 Kd gelatinase), MMP-7 (EC 3.4.24.23)
(matrylisin), MMP-8 (EC 3.4.24.34) (neutrophil collagenase), MMP-3
(EC 3.4.24.17) (stromelysin-1), MMP-10 (EC 3.4.24.22) (stromelysin-2), and
MMP-11 (stromelysin-3), MMP-12 (EC 3.4.24.65) (macrophage metalloelastase).
- Sea urchin hatching enzyme (envelysin) (EC 3.4.24.12). A protease that
allows the embryo to digest the protective envelope derived from the egg
extracellular matrix.
- Soybean metalloendoproteinase 1.
Family M11
- Chlamydomonas reinhardtii gamete lytic enzyme (GLE).
Family M12A
- Astacin (EC 3.4.24.21), a crayfish endoprotease.
- Meprin A (EC 3.4.24.18), a mammalian kidney and intestinal brush border
metalloendopeptidase.
- Bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and
bone formation and which expresses metalloendopeptidase activity. The
Drosophila homolog of BMP-1 is the dorsal-ventral patterning protein
tolloid.
- Blastula protease 10 (BP10) from Paracentrotus lividus and the related
protein SpAN from Strongylocentrotus purpuratus.
- Caenorhabditis elegans protein toh-2.
- Caenorhabditis elegans hypothetical protein F42A10.8.
- Choriolysins L and H (EC 3.4.24.67) (also known as embryonic hatching
proteins LCE and HCE) from the fish Oryzias lapides. These proteases
participates in the breakdown of the egg envelope, which is derived from
the egg extracellular matrix, at the time of hatching.
Family M12B
- Snake venom metalloproteinases [6]. This subfamily mostly groups proteases
that act in hemorrhage. Examples are: adamalysin II (EC 3.4.24.46),
atrolysin C/D (EC 3.4.24.42), atrolysin E (EC 3.4.24.44), fibrolase
(EC 3.4.24.72), trimerelysin I (EC 3.4.24.52) and II (EC 3.4.24.53).
- Mouse cell surface antigen MS2.
Family M13
- Mammalian neprilysin (EC 3.4.24.11) (neutral endopeptidase) (NEP).
- Endothelin-converting enzyme 1 (EC 3.4.24.71) (ECE-1), which process the
precursor of endothelin to release the active peptide.
- Kell blood group glycoprotein, a major antigenic protein of erythrocytes.
The Kell protein is very probably a zinc endopeptidase.
- Peptidase O from Lactococcus lactis (gene pepO).
Family M27
- Clostridial neurotoxins, including tetanus toxin (TeTx) and the various
botulinum toxins (BoNT). These toxins are zinc proteases that block
neurotransmitter release by proteolytic cleavage of synaptic proteins such
as synaptobrevins, syntaxin and SNAP-25 [7,8].
Family M30
- Staphylococcus hyicus neutral metalloprotease.
Family M32
- Thermostable carboxypeptidase 1 (EC 3.4.17.19) (carboxypeptidase Taq), an
enzyme from Thermus aquaticus which is most active at high temperature.
Family M34
- Lethal factor (LF) from Bacillus anthracis, one of the three proteins
composing the anthrax toxin.
Family M35
- Deuterolysin (EC 3.4.24.39) from Penicillium citrinum and related proteases
from various species of Aspergillus.
Family M36
- Extracellular elastinolytic metalloproteinases from Aspergillus.
From the tertiary structure of thermolysin, the position of the residues
acting as zinc ligands and those involved in the catalytic activity are known.
Two of the zinc ligands are histidines which are very close together in the
sequence; C-terminal to the first histidine is a glutamic acid residue which
acts as a nucleophile and promotes the attack of a water molecule on the
carbonyl carbon of the substrate. A signature pattern which includes the two
histidine and the glutamic acid residues is sufficient to detect this
superfamily of proteins.
-Consensus pattern: [GSTALIVN]-{PCHR}-{KND}-H-E-[LIVMFYW]-{DEHRKP}-H-{EKPC}-
[LIVMFYWGSPQ]
[The 2 H's are zinc ligands]
[E is the active site residue]
-Sequences known to belong to this class detected by the pattern: ALL, except
for members of families M5, M7 amd M11.
-Other sequence(s) detected in Swiss-Prot: 77; including Neurospora crassa
conidiation-specific protein 13 which could be a zinc-protease.
-Last update: April 2006 / Pattern revised.
[ 1] Jongeneel C.V., Bouvier J., Bairoch A.
"A unique signature identifies a family of zinc-dependent
metallopeptidases."
FEBS Lett. 242:211-214(1989).
PubMed=2914602
[ 2] Murphy G.J.P., Murphy G., Reynolds J.J.
"The origin of matrix metalloproteinases and their familial
relationships."
FEBS Lett. 289:4-7(1991).
PubMed=1894005
[ 3] Bode W., Grams F., Reinemer P., Gomis-Rueth F.-X., Baumann U.,
McKay D.B., Stoecker W.
Zoology 99:237-246(1996).
[ 4] Rawlings N.D., Barrett A.J.
"Evolutionary families of metallopeptidases."
Methods Enzymol. 248:183-228(1995).
PubMed=7674922
[ 5] Woessner J.F. Jr.
"Matrix metalloproteinases and their inhibitors in connective tissue
remodeling."
FASEB J. 5:2145-2154(1991).
PubMed=1850705
[ 6] Hite L.A., Fox J.W., Bjarnason J.B.
"A new family of proteinases is defined by several snake venom
metalloproteinases."
Biol. Chem. Hoppe-Seyler 373:381-385(1992).
PubMed=1515064
[ 7] Montecucco C., Schiavo G.
"Tetanus and botulism neurotoxins: a new group of zinc proteases."
Trends Biochem. Sci. 18:324-327(1993).
PubMed=7901925
[ 8] Niemann H., Blasi J., Jahn R.
"Clostridial neurotoxins: new tools for dissecting exocytosis."
Trends Cell Biol. 4:179-185(1994).
PubMed=14731646
[E1] https://www.uniprot.org/docs/peptidas
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