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	PROSITE documentation PDOC00130 [for PROSITE entry PS00143]

Insulinase family, zinc-binding region signature

A number of proteases dependent on divalent cations for their activity have been shown [1,2] to belong to one family, on the basis of sequence similarity. These enzymes are listed below.

• Insulinase (EC 3.4.24.56) (also known as insulysin or insulin-degrading enzyme or IDE), a cytoplasmic enzyme which seems to be involved in the cellular processing of insulin, glucagon and other small polypeptides.
• Escherichia coli protease III (EC 3.4.24.55) (pitrilysin) (gene ptr), a periplasmic enzyme that degrades small peptides.
• Mitochondrial processing peptidase (EC 3.4.24.64) (MPP). This enzyme removes the transit peptide from the precursor form of proteins imported from the cytoplasm across the mitochondrial inner membrane. It is composed of two nonidentical homologous subunits termed α and β. The β subunit seems to be catalytically active while the α subunit has probably lost its activity.
• Nardilysin (EC 3.4.24.61) (N-arginine dibasic convertase or NRD convertase) this mammalian enzyme cleaves peptide substrates on the N-terminus of Arg residues in dibasic stretches.
• Klebsiella pneumoniae protein pqqF. This protein is required for the biosynthesis of the coenzyme pyrrolo-quinoline-quinone (PQQ). It is thought to be protease that cleaves peptide bonds in a small peptide (gene pqqA) thus providing the glutamate and tyrosine residues necessary for the synthesis of PQQ.
• Yeast protein AXL1, which is involved in axial budding [3].
• Eimeria bovis sporozoite developmental protein.
• Escherichia coli hypothetical protein yddC and HI1368, the corresponding Haemophilus influenzae protein.
• Bacillus subtilis hypothetical protein ymxG.
• Caenorhabditis elegans hypothetical proteins C28F5.4 and F56D2.1.

It should be noted that in addition to the above enzymes, this family also includes the core proteins I and II of the mitochondrial bc1 complex (also called cytochrome c reductase or complex III), but the situation as to the activity or lack of activity of these subunits is quite complex:

• In mammals and yeast, core proteins I and II lack enzymatic activity.
• In Neurospora crassa and in potato core protein I is equivalent to the β subunit of MPP.
• In Euglena gracilis, core protein I seems to be active, while subunit II is inactive.

These proteins do not share many regions of sequence similarity; the most noticeable is in the N-terminal section. This region includes a conserved histidine followed, two residues later by a glutamate and another histidine. In pitrilysin, it has been shown [4] that this H-x-x-E-H motif is involved in enzyme activity; the two histidines bind zinc and the glutamate is necessary for catalytic activity. Non active members of this family have lost from one to three of these active site residues. We developed a signature pattern that detect active members of this family as well as some inactive members.

Note:

These proteins belong to family M16 in the classification of peptidases [5,E1].

Last update:

May 2004 / Text revised.

PROSITE method (with tools and information) covered by this documentation:

INSULINASE, PS00143; Insulinase family, zinc-binding region signature  (PATTERN)

• Consensus pattern:
  G-x(8,9)-G-x-[STA]-H-[LIVMFY]-[LIVMC]-[DERN]-[HRKL]-[LMFAT]-x-[LFSTH]-x-[GSTAN]-[GST]
  The 2 H's are zinc ligands; E is the active site residue
• Sequences in UniProtKB/Swiss-Prot known to belong to this class: 113
  • detected by PS00143: 73 (true positives)
  • undetected by PS00143: 40 (40 false negatives and 0 'partial')
• Other sequence(s) in UniProtKB/Swiss-Prot detected by PS00143:
  NONE.
• Retrieve an alignment of UniProtKB/Swiss-Prot true positive hits:
  Clustal format, color, condensed view  /  Clustal format, color  /  Clustal format, plain text  /  Fasta format
• Retrieve the sequence logo from the alignment
• Taxonomic distribution of all UniProtKB (Swiss-Prot + TrEMBL) entries matching PS00143
• Retrieve a list of all UniProtKB (Swiss-Prot + TrEMBL) entries matching PS00143
• Scan UniProtKB (Swiss-Prot and/or TrEMBL) entries against PS00143
• View ligand binding statistics of PS00143
• Matching PDB structures: 1BCC 1BE3 1BGY 1EZV ... [ALL]

1	Authors	Rawlings N.D., Barrett A.J.
	Title	Homologues of insulinase, a new superfamily of metalloendopeptidases.
	Source	Biochem. J. 275:389-391(1991).
	PubMed ID	2025223

2	Authors	Braun H.-P., Schmitz U.K.
	Title	Are the 'core' proteins of the mitochondrial bc1 complex evolutionary relics of a processing protease?
	Source	Trends Biochem. Sci. 20:171-175(1995).
	PubMed ID	7610476

3	Authors	Becker A.B., Roth R.A.
	Title	An unusual active site identified in a family of zinc metalloendopeptidases.
	Source	Proc. Natl. Acad. Sci. U.S.A. 89:3835-3839(1992).
	PubMed ID	1570301

4	Authors	Fujita A., Oka C., Arikawa Y., Katagai T., Tonouchi A., Kuhara S., Misumi Y.
	Title	A yeast gene necessary for bud-site selection encodes a protein similar to insulin-degrading enzymes.
	Source	Nature 372:567-570(1994).
	PubMed ID	7990931
	DOI	10.1038/372567a0

5	Authors	Rawlings N.D., Barrett A.J.
	Title	Evolutionary families of metallopeptidases.
	Source	Methods Enzymol. 248:183-228(1995).
	PubMed ID	7674922

E1	Title	https://www.uniprot.org/docs/peptidas
	Source	?

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