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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] in
the part of  their  sequence involved  in the   binding  of  zinc, and can  be
grouped together as  a family  on the basis  of  this sequence similarity. The
proteases which are currently  known to belong to this family are listed below
(references are only provided for recently determined sequences).

 - Mammalian extracellular matrix metalloproteinases (known as matrixins) [3]:
   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).
 - Mammalian neprilysin (EC 3.4.24.11) (neutral endopeptidase) (NEP).
 - Astacin (EC 3.4.24.21), a crayfish endoprotease.
 - Meprin A  (EC 3.4.24.18), a mammalian  kidney  and intestinal brush  border
   metalloendopeptidase.
 - Thimet  oligopeptidase  (EC 3.4.24.15),  a mammalian enzyme involved in the
   cytoplasmic degradation of small peptides.
 - PABA-peptide hydrolase, a human intestine membrane protease.
 - Yeast saccharolysin (EC 3.4.24.37) (proteinase yscD) [4].
 - 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 [5].
 - Mammalian aminopeptidase N (EC 3.4.11.2).
 - Yeast aminopeptidase yscII.
 - Mammalian glutamyl aminopeptidase (EC 3.4.11.7) (BP-1/6C3 antigen).  It may
   play a role in  regulating growth  and  differentiation  of early B-lineage
   cells.
 - 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.
 - Snake venom metalloproteinases [6].  This subfamily mostly groups proteases
   that  act  in  hemorrhage.   Examples  are:  atrolysin C/D  (EC 3.4.24.42),
   trimerelysin I (EC 3.4.25.52) and II (EC 3.4.25.53).
 - 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.
 - Embryonic hatching proteins LCE and HCE from the fish Oryzias lapides.
 - Chlamydomonas reinhardtii gamete lytic enzyme (GLE) [7].
 - Kell blood group  glycoprotein [8], a  major  antigenic  protein  of  Human
   erythrocytes. The Kell protein is very probably a zinc endopeptidase.
 - 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.
 - Leishmanolysin (EC 3.4.24.36) (surface glycoprotein gp63),  a  cell surface
   protease from various species of Leishmania.

 - 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).
 - Serralysin (EC 3.4.24.40), an extracellular metalloprotease from Serratia.
 - Secreted proteases B and C from Erwinia chrysanthemi.
 - Extracellular proteinase proA from Legionella pneumophila.
 - Immune inhibitor A from Bacillus thuringiensis (gene ina). Ina degrades two
   classes of insect antibacterial proteins, attacins and cecropins.
 - Extracellular neutral metalloprotease from Streptomyces cacaoi.
 - Escherichia coli  and  Salmonella typhiumurium  dipeptidyl carboxypeptidase
   (gene dcd).
 - Escherichia coli and Salmonella typhiumurium oligopeptidase A (gene opdA or
   prlC).
 - Escherichia coli aminopeptidase N (gene pepN).

 - 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 synaptobrevins [9].

 - 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
   [10] that it binds zinc and is capable of peptidase activity.

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 family
of proteins.

-Consensus pattern: [STALIV]-x(2)-H-E-[LIVMFYW]-{DEHRKP}-H-x-[LIVMFYWGQ]
                    [The two 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 the Streptomyces cacaoi protease which has Ala in  the position following
 the active site Glu.
-Other sequence(s) detected in SWISS-PROT: 17;  including   Neurospora  crassa
 conidiation-specific protein 13 [11] which could be a zinc-protease.
-Last update: June 1994 / Text revised.

[ 1] Jongeneel C.V., Bouvier J., Bairoch A.
     FEBS Lett. 242:211-214(1989).
[ 2] Murphy G.J.P., Murphy G., Reynolds J.J.
     FEBS Lett. 289:4-7(1991).
[ 3] Woessner J. Jr.
     FASEB J. 5:2145-2154(1991).
[ 4] Buchler M., Tisljar U., Wolf D.H.
     Eur. J. Biochem. 219:627-639(1994).
[ 5] Ehlers M.R., Riordan J.F.
     Biochemistry 30:7118-7126(1991).
[ 6] Hite L.A., Fox J.W., Bjarnason J.B.
     Biol. Chem. Hoppe-Seyler 373:381-385(1992).
[ 7] Kinoshita T., Fukuzawa H., Shimada T., Saito T., Matsuda Y.
     Proc. Natl. Acad. Sci. U.S.A. 89:4693-4697(1992).
[ 8] Lee S., Zambas E.D., Marsh W.L., Redman C.M.
     Proc. Natl. Acad. Sci. U.S.A. 88:6353-6357(1991).
[ 9] Montecucco C., Schiavo G.
     Trends Biochem. Sci. 18:324-327(1993).
[10] Medina J.F., Wetterholm A., Radmark O., Shapiro R., Haeggstroem J.Z.,
     Vallee B.L., Samuelsson B.
     Proc. Natl. Acad. Sci. U.S.A. 88:7620-7624(1991).
[11] Hager K.M., Yanofsky C.
     Gene 96:153-159(1990).