Mitochondrial processing peptidase
Identifiers
EC no.3.4.24.64
CAS no.86280-61-7
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Mitochondrial processing peptidase is an enzyme complex found in mitochondria which cleaves signal sequences from mitochondrial proteins. In humans this complex is composed of two subunits encoded by the genes PMPCA, and PMPCB. The enzyme is also known as (EC 3.4.24.64, processing enhancing peptidase (for one of two subunits), mitochondrial protein precursor-processing proteinase, matrix peptidase, matrix processing peptidase, matrix processing proteinase, or MPP).[1][2][3][4][5] This enzyme catalyses the following chemical reaction

Release of N-terminal targeting peptides from precursor proteins imported into the mitochondrion, typically with Arg in position P2

This enzyme is present the mitochondrial matrix of fungi and mammals.

Function

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.[6]

In most eukaryotes, the MPP consists of two subunits, an α and β subunit which bind together to form a heterodimeric complex.[7] 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,[8] 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.[9]

Structure and Mechanism

The X-ray structures of yeast MPP, and a cleavage-deficient MPP with substrate bound, are available.[10] 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).

Evolution

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.[11] Experimentally this peptidase was shown to cleave signal sequences from mitochondrial proteins.[12]

See also

References

  1. ↑ Jensen, R.E.; Yaffe, M.P. (1988). "Import of proteins into yeast mitochondria: the nuclear MAS2 gene encodes a component of the processing protease that is homologous to the MAS1-encoded subunit". EMBO J. 7 (12): 3863–3871. doi:10.1002/j.1460-2075.1988.tb03272.x. PMC 454965. PMID 3061808.
  2. ↑ Witte, C.; Jensen, R.E.; Yaffe, M.P.; Schatz, G. (1988). "MAS1, a gene essential for yeast mitochondrial assembly, encodes a subunit of the mitochondrial processing protease". EMBO J. 7 (5): 1439–1447. doi:10.1002/j.1460-2075.1988.tb02961.x. PMC 458394. PMID 3044780.
  3. ↑ Rawlings, N.D.; Barrett, A.J. (1991). "Homologues of insulinase, a new superfamily of metalloendopeptidases". Biochem. J. 275 (2): 389–391. doi:10.1042/bj2750389. PMC 1150065. PMID 2025223.
  4. ↑ Kalousek, F.; Neupert, W.; Omura, T.; Schatz, G.; Schmitz, U.K. (1993). "Uniform nomenclature for the mitochondrial peptidases cleaving precursors of mitochondrial proteins". Trends Biochem. Sci. 18 (7): 249. doi:10.1016/0968-0004(93)90174-l. PMID 8212133.
  5. ↑ Brunner, M.; Neupert, W. (1995). Proteolytic Enzymes: Aspartic and Metallo Peptidases Purification and characterization of mitochondrial processing peptidase of Neurospora crassa. Methods in Enzymology. Vol. 248. pp. 717–728. doi:10.1016/0076-6879(95)48048-x. ISBN 9780121821494. PMID 7674958.
  6. ↑ Koutnikova H, Campuzano V, Koenig M (1998). "Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase". Human Molecular Genetics. 7 (9): 1485–9. doi:10.1093/hmg/7.9.1485. PMID 9700204.
  7. ↑ Taylor AB, Smith BS, Kitada S, Kojima K, Miyaura H, Otwinowski Z, Ito A, Deisenhofer J (2001). "Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences". Structure. 9 (7): 615–25. doi:10.1016/s0969-2126(01)00621-9. PMID 11470436.
  8. ↑ Adamec J, Gakh O, Spizek J, Kalousek F (1999). "Complementation between mitochondrial processing peptidase (MPP) subunits from different species". Archives of Biochemistry and Biophysics. 370 (1): 77–85. doi:10.1006/abbi.1999.1397. PMID 10496979.
  9. ↑ Brown MT, Goldstone HM, Bastida-Corcuera F, Delgadillo-Correa MG, McArthur AG, Johnson PJ (2007). "A functionally divergent hydrogenosomal peptidase with protomitochondrial ancestry". Mol. Microbiol. 64 (5): 1154–63. doi:10.1111/j.1365-2958.2007.05719.x. PMID 17542912.
  10. ↑ A B Taylor, B S Smith, S Kitada, K Kojima, H Miyaura, Z Otwinowski, A Ito, J Deisenhofer (2001). "Crystal structures of mitochondrial processing peptidase reveal the mode for specific cleavage of import signal sequences". Structure. 9: 615–625. doi:10.1016/s0969-2126(01)00621-9. PMID 11470436.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ Emelyanov VV (2001). "Rickettsiaceae, rickettsia-like endosymbionts, and the origin of mitochondria". Biosci. Rep. 21 (1): 1–17. doi:10.1023/A:1010409415723. PMID 11508688.
  12. ↑ Kitada S, Uchiyama T, Funatsu T, Kitada Y, Ogishima T, Ito A (2007). "A protein from a parasitic microorganism, Rickettsia prowazekii, can cleave the signal sequences of proteins targeting mitochondria". J. Bacteriol. 189 (3): 844–50. doi:10.1128/JB.01261-06. PMC 1797283. PMID 17158683.
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