Mitochondrial processing peptidase

Mitochondria import the majority of their proteins from the cell cytosol. In order to achieve this, many mitochondrial proteins encode a short targeting signal which directs them to the mitochondrion and through its preprotein translocase machinery. Mitochondrial proteins which reach the innermost mitochondrial compartment, the Mitochondrial matrix, often undergo proteolytic cleavage of the targeting signal, performed by the Mitochondrial Processing Peptidase (MPP), this is often necessary for the maturation of the preprotein to its functional form or to reveal additional targeting sequences.

{{cite journal|vauthors=Koutnikova H, Campuzano V, Koenig M |title=Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase.|journal=Human Molecular Genetics|year=1998|volume=7|issue=9|pages=1485–9|pmid=9700204|doi=10.1093/hmg/7.9.1485|doi-access=free}}

In most eukaryotes, the MPP consists of two subunits, an α and β subunit which bind together to form a heterodimeric complex.{{cite journal|vauthors=Taylor AB, Smith BS, Kitada S, Kojima K, Miyaura H, Otwinowski Z, Ito A, Deisenhofer J |title=Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences.|journal=Structure|year=2001|volume=9|issue=7|pages=615–25|pmid=11470436|doi=10.1016/s0969-2126(01)00621-9|doi-access=free}} In humans these are the genes PMPCA and PMPCB. The subunits of the MPP are highly conserved, and have shown to be interoperable between species,{{cite journal|vauthors=Adamec J, Gakh O, Spizek J, Kalousek F |title=Complementation between mitochondrial processing peptidase (MPP) subunits from different species.|journal=Archives of Biochemistry and Biophysics|year=1999|volume=370|issue=1|pages=77–85|pmid=10496979|doi=10.1006/abbi.1999.1397}} homologues to MPPs are also found in eukaryotes whose mitochondria have evolved into divergent organelles, though in the case of Trichomonas the processing peptidase complex appears to be made of two β subunits.{{cite journal |vauthors=Brown MT, Goldstone HM, Bastida-Corcuera F, Delgadillo-Correa MG, McArthur AG, Johnson PJ |title=A functionally divergent hydrogenosomal peptidase with protomitochondrial ancestry |journal=Mol. Microbiol. |volume=64 |issue=5 |pages=1154–63 |year=2007 |doi=10.1111/j.1365-2958.2007.05719.x |pmid=17542912|doi-access=free }}

The X-ray structures of yeast MPP, and a cleavage-deficient MPP with substrate bound, are available.{{cite journal |title=Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences|author = A B Taylor, B S Smith, S Kitada, K Kojima, H Miyaura, Z Otwinowski, A Ito, J Deisenhofer| journal = Structure | volume = 9 | pages = 615–625 | year = 2001 | PMID = 11470436| DOI = 10.1016/s0969-2126(01)00621-9 | doi-access = free }} The sequence around the scissile bond binds as a beta strand in such a way that the scissile bond aligns with the zinc binding site to allow nucleophilic attack by a zinc—coordinated water molecule on the carbonyl carbon of the residue before the scissile bond (last residue of the signal peptide).

The origins of the mitochondrial processing peptidases are thought to be prokaryotic in origin, possibly originating in the endosymbiont which developed into the mitochondrion, this hypothesis has been supported by the discovery of a bacterial signal peptidase in Rickettsia, an organism thought to be a closely related to the mitochondrial progenitor.{{cite journal |vauthors=Emelyanov VV |title=Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria |journal=Biosci. Rep. |volume=21 |issue=1 |pages=1–17 |year=2001 |doi= 10.1023/A:1010409415723|pmid=11508688}} Experimentally this peptidase was shown to cleave signal sequences from mitochondrial proteins.{{cite journal |vauthors=Kitada S, Uchiyama T, Funatsu T, Kitada Y, Ogishima T, Ito A |title=A protein from a parasitic microorganism, Rickettsia prowazekii, can cleave the signal sequences of proteins targeting mitochondria |journal=J. Bacteriol. |volume=189 |issue=3 |pages=844–50 |year=2007 |pmid=17158683 |pmc=1797283 |doi=10.1128/JB.01261-06 }}

• Translocase of the outer membrane
• Signal peptidase
• PMPCA
• PMPCB

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• {{MeshName|Mitochondrial+processing+peptidase}}

{{Metalloendopeptidases}}

{{Enzymes}}

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Category:EC 3.4.24