Mitochondrial processing peptidase

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Mitochondrial processing peptidase
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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

Contents

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

Related Research Articles

<span class="mw-page-title-main">Mitochondrion</span> Organelle in eukaryotic cells responsible for respiration

A mitochondrion is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. They were discovered by Albert von Kölliker in 1857 in the voluntary muscles of insects. The term mitochondrion was coined by Carl Benda in 1898. The mitochondrion is popularly nicknamed the "powerhouse of the cell", a phrase coined by Philip Siekevitz in a 1957 article of the same name.

Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular membranes, the plasma membrane, or to the exterior of the cell via secretion. Information contained in the protein itself directs this delivery process. Correct sorting is crucial for the cell; errors or dysfunction in sorting have been linked to multiple diseases.

<span class="mw-page-title-main">Cytochrome c oxidase</span> Complex enzyme found in bacteria, archaea, and mitochondria of eukaryotes

The enzyme cytochrome c oxidase or Complex IV, is a large transmembrane protein complex found in bacteria, archaea, and the mitochondria of eukaryotes.

In molecular biology, the Signal Peptide Peptidase (SPP) is a type of protein that specifically cleaves parts of other proteins. It is an intramembrane aspartyl protease with the conserved active site motifs 'YD' and 'GxGD' in adjacent transmembrane domains (TMDs). Its sequences is highly conserved in different vertebrate species. SPP cleaves remnant signal peptides left behind in membrane by the action of signal peptidase and also plays key roles in immune surveillance and the maturation of certain viral proteins.

<span class="mw-page-title-main">TIM/TOM complex</span>

The TIM/TOM complex is a protein complex in cellular biochemistry which translocates proteins produced from nuclear DNA through the mitochondrial membrane for use in oxidative phosphorylation. In enzymology, the complex is described as an mitochondrial protein-transporting ATPase, or more systematically ATP phosphohydrolase , as the TIM part requires ATP hydrolysis to work.

<span class="mw-page-title-main">Mitochondrial membrane transport protein</span>

Mitochondrial membrane transport proteins, also known as mitochondrial carrier proteins, are proteins which exist in the membranes of mitochondria. They serve to transport molecules and other factors, such as ions, into or out of the organelles. Mitochondria contain both an inner and outer membrane, separated by the inter-membrane space, or inner boundary membrane. The outer membrane is porous, whereas the inner membrane restricts the movement of all molecules. The two membranes also vary in membrane potential and pH. These factors play a role in the function of mitochondrial membrane transport proteins. There are 53 discovered human mitochondrial membrane transporters, with many others that are known to still need discovered.

<span class="mw-page-title-main">TOMM20</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import receptor subunit TOM20 homolog is a protein that in humans is encoded by the TOMM20 gene. TOM20 is one of the receptor systems of the TOM complex in the outer mitochondrial membrane (OMM).

<span class="mw-page-title-main">TOMM22</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import receptor subunit TOM22 homolog is a protein that in humans is encoded by the TOMM22 gene.

<span class="mw-page-title-main">Translocase of the outer membrane</span>

The translocase of the outer membrane (TOM) is a complex of proteins found in the outer mitochondrial membrane of the mitochondria. It allows movement of proteins through this barrier and into the intermembrane space of the mitochondrion. Most of the proteins needed for mitochondrial function are encoded by the nucleus of the cell. The outer membrane of the mitochondrion is impermeable to large molecules greater than 5000 daltons. The TOM works in conjunction with the translocase of the inner membrane (TIM) to translocate proteins into the mitochondrion. Many of the proteins in the TOM complex, such as TOMM22, were first identified in Neurospora crassa and Saccharomyces cerevisiae. Many of the genes encoding these proteins are designated as TOMM (translocase of the outer mitochondrial membrane) complex genes.

<span class="mw-page-title-main">PMPCB</span> Protein-coding gene in humans

Mitochondrial-processing peptidase subunit beta is an enzyme that in humans is encoded by the PMPCB gene. This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.

<span class="mw-page-title-main">PMPCA</span> Protein-coding gene in humans

Mitochondrial-processing peptidase subunit alpha is an enzyme that in humans is encoded by the PMPCA gene. This gene PMPCA encoded a protein that is a member of the peptidase M16 family. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.

<span class="mw-page-title-main">TIMM44</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit TIM44 is an enzyme that in humans is encoded by the TIMM44 gene.

<span class="mw-page-title-main">TIMM23</span> Protein-coding gene in the species Homo sapiens

Mitochondrial import inner membrane translocase subunit Tim23 is an enzyme that in humans is encoded by the TIMM23 gene.

<span class="mw-page-title-main">ATP-dependent Clp protease proteolytic subunit</span> Protein-coding gene in the species Homo sapiens

ATP-dependent Clp protease proteolytic subunit (ClpP) is an enzyme that in humans is encoded by the CLPP gene. This protein is an essential component to form the protein complex of Clp protease.

The translocase of the inner membrane (TIM) is a complex of proteins found in the inner mitochondrial membrane of the mitochondria. Components of the TIM complex facilitate the translocation of proteins across the inner membrane and into the mitochondrial matrix. They also facilitate the insertion of proteins into the inner mitochondrial membrane, where they must reside in order to function, these mainly include members of the mitochondrial carrier family of proteins.

<span class="mw-page-title-main">Signal peptidase</span>

Signal peptidases are enzymes that convert secretory and some membrane proteins to their mature or pro forms by cleaving their signal peptides from their N-termini.

A target peptide is a short peptide chain that directs the transport of a protein to a specific region in the cell, including the nucleus, mitochondria, endoplasmic reticulum (ER), chloroplast, apoplast, peroxisome and plasma membrane. Some target peptides are cleaved from the protein by signal peptidases after the proteins are transported.

<span class="mw-page-title-main">OMA1</span> Protein-coding gene in the species Homo sapiens

Metalloendopeptidase OMA1, mitochondrial is an enzyme that in humans is encoded by the OMA1 gene. OMA1 is a Zn2+-dependent metalloendopeptidase in the inner membrane of mitochondria. The OMA1 acronym was derived from overlapping proteolytic activity with m-AAA protease 1.

<span class="mw-page-title-main">MIPEP</span> Protein-coding gene in the species Homo sapiens

Mitochondrial intermediate peptidase is an enzyme that in humans is encoded by the MIPEP gene. This protein is a critical component of human mitochondrial protein import machinery involved in the maturing process of nuclear coded mitochondrial proteins that with a mitochondrial translocation peptide, especially those OXPHOS-related proteins.

The mitochondrial unfolded protein response (UPRmt) is a cellular stress response related to the mitochondria. The UPRmt results from unfolded or misfolded proteins in mitochondria beyond the capacity of chaperone proteins to handle them. The UPRmt can occur either in the mitochondrial matrix or in the mitochondrial inner membrane. In the UPRmt, the mitochondrion will either upregulate chaperone proteins or invoke proteases to degrade proteins that fail to fold properly. UPRmt causes the sirtuin SIRT3 to activate antioxidant enzymes and mitophagy.

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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