Metalloproteinase

A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example of this would be ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myogenesis.

Peptidase_M48
Identifiers
SymbolPeptidase_M48
PfamPF01435
Pfam clanCL0126
InterProIPR001915
MEROPSM48
OPM superfamily394
OPM protein4aw6
Membranome317
Peptidase_M50
Identifiers
SymbolPeptidase_M50
PfamPF02163
Pfam clanCL0126
InterProIPR008915
MEROPSM50
OPM superfamily184
OPM protein3b4r

Most metalloproteases require zinc, but some use cobalt. The metal ion is coordinated to the protein via three ligands. The ligands co-ordinating the metal ion can vary with histidine, glutamate, aspartate, lysine, and arginine. The fourth coordination position is taken up by a labile water molecule.

Treatment with chelating agents such as EDTA leads to complete inactivation. EDTA is a metal chelator that removes zinc, which is essential for activity. They are also inhibited by the chelator orthophenanthroline.

Classification

There are two subgroups of metalloproteinases:

In the MEROPS database peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding.

Metalloproteases are the most diverse of the four main protease types, with more than 50 families classified to date. In these enzymes, a divalent cation, usually zinc, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. The known metal ligands are His, Glu, Asp or Lys and at least one other residue is required for catalysis, which may play an electrophillic role. Of the known metalloproteases, around half contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site.[3] The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue.[4] Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases.[3]

Metallopeptidases from family M48 are integral membrane proteins associated with the endoplasmic reticulum and Golgi, binding one zinc ion per subunit. These endopeptidases include CAAX prenyl protease 1, which proteolytically removes the C-terminal three residues of farnesylated proteins.

Metalloproteinase inhibitors are found in numerous marine organisms, including fish, cephalopods, mollusks, algae and bacteria.[5]

Members of the M50 metallopeptidase family include: mammalian sterol-regulatory element binding protein (SREBP) site 2 protease and Escherichia coli protease EcfE, stage IV sporulation protein FB.

gollark: It just does nonsense and downloads another program.
gollark: I'll inspect the code actually.
gollark: Don't do it.
gollark: I mean, in theory you could send messages on "secure" channels or whatever.
gollark: This is mostly the case, except I can block messages and stuff and they can't (in theory; I don't do this).

See also

References
  1. Shen, Yuequan; Joachimiak, Andrzej; Rosner, Marsha Rich; Tang, Wei-Jen (2006-10-19). "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature. 443 (7113): 870–874. Bibcode:2006Natur.443..870S. doi:10.1038/nature05143. ISSN 1476-4687. PMC 3366509. PMID 17051221.
  2. King, John V.; Liang, Wenguang G.; Scherpelz, Kathryn P.; Schilling, Alexander B.; Meredith, Stephen C.; Tang, Wei-Jen (2014-07-08). "Molecular basis of substrate recognition and degradation by human presequence protease". Structure. 22 (7): 996–1007. doi:10.1016/j.str.2014.05.003. ISSN 1878-4186. PMC 4128088. PMID 24931469.
  3. Rawlings ND, Barrett AJ (1995). "Evolutionary families of metallopeptidases". Methods in Enzymology. 248: 183–228. doi:10.1016/0076-6879(95)48015-3. ISBN 978-0-12-182149-4. PMID 7674922. Cite journal requires |journal= (help)
  4. Minde DP, Maurice MM, Rüdiger SG (2012). "Determining biophysical protein stability in lysates by a fast proteolysis assay, FASTpp". PLOS ONE. 7 (10): e46147. Bibcode:2012PLoSO...746147M. doi:10.1371/journal.pone.0046147. PMC 3463568. PMID 23056252.
  5. Thomas NV, Kim SK (2010). "Metalloproteinase inhibitors: status and scope from marine organisms". Biochemistry Research International. 2010: 845975. doi:10.1155/2010/845975. PMC 3004377. PMID 21197102.
This article incorporates text from the public domain Pfam and InterPro: IPR008915
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