PPIF

Last updated
PPIF
Protein PPIF PDB 2bit.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PPIF , CYP3, CyP-M, Cyp-D, CypD, peptidylprolyl isomerase F
External IDs OMIM: 604486 MGI: 2145814 HomoloGene: 38696 GeneCards: PPIF
Orthologs
SpeciesHumanMouse
Entrez

10105

105675

Ensembl

ENSG00000108179

ENSMUSG00000021868

UniProt

P30405

Q99KR7

RefSeq (mRNA)

NM_005729

NM_134084

RefSeq (protein)

NP_005720

NP_598845

Location (UCSC) Chr 10: 79.35 – 79.36 Mb Chr 14: 25.69 – 25.7 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Peptidyl-prolyl cis-trans isomerase, mitochondrial (PPIF) is an enzyme that in humans is encoded by the PPIF gene. It has also been referred to as, but should not be confused with, cyclophilin D (CypD), which is encoded by the PPID gene. [5] [6] As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. [6] PPIF is a major component of the mitochondrial permeability transition pore (MPTP) and, thus, highly involved in mitochondrial metabolism and apoptosis, as well as in mitochondrial diseases and related conditions, including cardiac diseases, neurodegenerative diseases, and muscular dystrophy. [7] In addition, PPIF participates in inflammation, as well as in ischemic reperfusion injury, AIDS, and cancer. [8] [9] [10] [11]

Structure

Like other cyclophilins, PPIF forms a β-barrel structure with a hydrophobic core. This β-barrel is composed of eight anti-parallel β-strands and capped by two α-helices at the top and bottom. In addition, the β-turns and loops in the strands contribute to the flexibility of the barrel. [10] PPIF weighs 17.5 kDa and forms part of the MPTP in the inner mitochondrial membrane (IMM). [6] [12]

Function

The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. [6] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved. [8] [13] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). [8] [10] As a cyclophilin, PPI binds cyclosporin A (CsA) and can be found within the cell or secreted by the cell. [9] In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types, though studies on PPIF focus primarily on heart, liver, and brain tissue. [7] [9] [10] In addition to PPIase and protein chaperone activities, cyclophilins also function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. [8] [9] [10] PPIF is especially involved in mitochondrial apoptosis as a major component of the MPTP. Through its PPIase ability, the protein interacts with and induces a conformational change in adenine nucleotide translocase (ANT), the other MPTP component. This activation, along with high calcium ion levels, induces the opening the MPTP, resulting in mitochondrial swelling, increasing reactive oxygen species (ROS) levels, membrane depolarization, failing ATP production, caspase cascade activation, and ultimately, apoptosis. [14] [15] [16]

Clinical significance

As a cyclophilin, PPIF binds the immunosuppressive drug CsA to form a CsA-cyclophilin complex, which then targets calcineurin to inhibit the signaling pathway for T-cell activation. [9]

Due to its association with the MPTP, PPIF is also involved in neurodegenerative diseases, including glaucoma, diabetic retinopathy, Parkinson's disease, and Alzheimer's disease. [16] For neurodegenerative diseases, treatment of reperfusion events with CsA, a PPID inhibitor, prevents cytochrome C release and significantly reduces cell death in neurons. As such, PPID proves to be an effective therapeutic target for patients suffering neurodegenerative diseases.

In addition, PPIF, as part of the MPTP, is involved in ischemia/reperfusion injury, traumatic brain injury (TBI), muscular dystrophy, and drug toxicity. [7] Though PPIF was identified as a candidate for dilated cardiomyopathy (DCM) for one afflicted family, further study revealed no mutations in the gene to implicate it in the disease. [15] Nonetheless, in cardiac myogenic cells, cyclophilins have been observed to be activated by heat shock and hypoxia-reoxygenation as well as complex with heat shock proteins. Thus, cyclophilins may function in cardioprotection during ischemia-reperfusion injury.

Currently, cyclophilin expression is highly correlated with cancer pathogenesis, but the specific mechanisms remain to be elucidated. [9]

Interactions

PPIF has been shown to interact with:

Related Research Articles

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

Cyclophilins (CYPs) are a family of proteins named after their ability to bind to ciclosporin, an immunosuppressant which is usually used to suppress rejection after internal organ transplants. They are found in all domains of life. These proteins have peptidyl prolyl isomerase activity, which catalyzes the isomerization of peptide bonds from trans form to cis form at proline residues and facilitates protein folding.

<span class="mw-page-title-main">Prolyl isomerase</span> Enzyme

Prolyl isomerase is an enzyme found in both prokaryotes and eukaryotes that interconverts the cis and trans isomers of peptide bonds with the amino acid proline. Proline has an unusually conformationally restrained peptide bond due to its cyclic structure with its side chain bonded to its secondary amine nitrogen. Most amino acids have a strong energetic preference for the trans peptide bond conformation due to steric hindrance, but proline's unusual structure stabilizes the cis form so that both isomers are populated under biologically relevant conditions. Proteins with prolyl isomerase activity include cyclophilin, FKBPs, and parvulin, although larger proteins can also contain prolyl isomerase domains.

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

Parvulin, a 92-amino acid protein discovered in E. coli in 1994, is the smallest known protein with prolyl isomerase activity, which catalyzes the cis-trans isomerization of proline peptide bonds. Although parvulin has no homology with larger prolyl isomerases such as cyclophilin and FKBP, it does share structural features with subdomains of other proteins involved in preparing secreted proteins for export from the cell.

<span class="mw-page-title-main">Antamanide</span> Chemical compound

Antamanide is a cyclic decapeptide isolated from a fungus, the death cap: Amanita phalloides. It is being studied as a potential anti-toxin against the effects of phalloidin and for its potential for treating edema. It contains 1 valine residue, 4 proline residues, 1 alanine residue, and 4 phenylalanine residues with a structure of c(Val-Pro-Pro-Ala-Phe-Phe-Pro-Pro-Phe-Phe). It was isolated by determining the source of the anti-phalloidin activity from a lipophillic extraction from the organism. It has been shown that antamanide can react to form alkali metal ion complexes. These include complexes with sodium and calcium ions. When these complexes are formed, the cyclopeptide structure undergoes a conformational change.

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

Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the PPIA gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate many biological processes, including intracellular signaling, transcription, inflammation, and apoptosis. Due to its various functions, PPIA has been implicated in a broad range of inflammatory diseases, including atherosclerosis and arthritis, and viral infections.

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

Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.

<span class="mw-page-title-main">PIN1</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.

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

Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the PPID gene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPID participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.

<span class="mw-page-title-main">Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 4 is an enzyme that in humans is encoded by the PIN4 gene.

<span class="mw-page-title-main">PPIL1</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase-like 1 is an enzyme that in humans is encoded by the PPIL1 gene.

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

Peptidyl-prolyl cis-trans isomerase H is an enzyme that in humans is encoded by the PPIH gene.

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

Peptidyl-prolyl cis-trans isomerase C (PPIC) is an enzyme that in humans is encoded by the PPIC gene on chromosome 5. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIC participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.

<span class="mw-page-title-main">PPIL3</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase-like 3 is an enzyme that in humans is encoded by the PPIL3 gene.

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

Peptidyl-prolyl cis-trans isomerase G is an enzyme that in humans is encoded by the PPIG gene.

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

Peptidylprolyl isomerase E (cyclophilin E), also known as PPIE, is an enzyme which in humans is encoded by the PPIE gene on chromosome 1. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIE participates in many biological processes, including mitochondrial metabolism, apoptosis, and inflammation, as well as related diseases and conditions, such as ischemic reperfusion injury, AIDS, influenza, and cancer.

<span class="mw-page-title-main">PPIL2</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase-like 2 is an enzyme that in humans is encoded by the PPIL2 gene.

<span class="mw-page-title-main">PPIL4</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase-like 4 is an enzyme that in humans is encoded by the PPIL4 gene.

FK506 binding protein 7 is a protein that in humans is encoded by the FKBP7 gene. The gene is also known as FKBP23 and PPIase. FKBP7 belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase (PPIase) family. Members of this family exhibit PPIase activity and function as molecular chaperones. The orthologous protein in mouse is located in the endoplasmic reticulum and binds calcium.

In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

Par14 is a member of the parvulin family of peptidyl-prolyl-cis/trans-isomerases (PPIases) in humans, which possesses prolyl isomerase activity.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000108179 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000021868 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Bergsma DJ, Eder C, Gross M, Kersten H, Sylvester D, Appelbaum E, Cusimano D, Livi GP, McLaughlin MM, Kasyan K (Dec 1991). "The cyclophilin multigene family of peptidyl-prolyl isomerases. Characterization of three separate human isoforms". The Journal of Biological Chemistry. 266 (34): 23204–14. doi: 10.1016/S0021-9258(18)54484-7 . PMID   1744118.
  6. 1 2 3 4 "Entrez Gene: PPIF peptidylprolyl isomerase F (cyclophilin F)".
  7. 1 2 3 Hansson MJ, Morota S, Chen L, Matsuyama N, Suzuki Y, Nakajima S, Tanoue T, Omi A, Shibasaki F, Shimazu M, Ikeda Y, Uchino H, Elmér E (Jan 2011). "Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria". Journal of Neurotrauma. 28 (1): 143–53. doi:10.1089/neu.2010.1613. PMC   3025768 . PMID   21121808.
  8. 1 2 3 4 Kazui T, Inoue N, Yamada O, Komatsu S (Jan 1992). "Selective cerebral perfusion during operation for aneurysms of the aortic arch: a reassessment". The Annals of Thoracic Surgery. 53 (1): 109–14. doi: 10.1016/0003-4975(92)90767-x . PMID   1530810.
  9. 1 2 3 4 5 6 Yao Q, Li M, Yang H, Chai H, Fisher W, Chen C (Mar 2005). "Roles of cyclophilins in cancers and other organ systems". World Journal of Surgery. 29 (3): 276–80. doi:10.1007/s00268-004-7812-7. PMID   15706440. S2CID   11678319.
  10. 1 2 3 4 5 Wang T, Yun CH, Gu SY, Chang WR, Liang DC (Aug 2005). "1.88 A crystal structure of the C domain of hCyP33: a novel domain of peptidyl-prolyl cis-trans isomerase". Biochemical and Biophysical Research Communications. 333 (3): 845–9. doi:10.1016/j.bbrc.2005.06.006. PMID   15963461.
  11. ↑ Stocki P, Chapman DC, Beach LA, Williams DB (Aug 2014). "Depletion of cyclophilins B and C leads to dysregulation of endoplasmic reticulum redox homeostasis". The Journal of Biological Chemistry. 289 (33): 23086–96. doi: 10.1074/jbc.M114.570911 . PMC   4132807 . PMID   24990953.
  12. ↑ Jandova J, Janda J, Sligh JE (Mar 2013). "Cyclophilin 40 alters UVA-induced apoptosis and mitochondrial ROS generation in keratinocytes". Experimental Cell Research. 319 (5): 750–60. doi:10.1016/j.yexcr.2012.11.016. PMC   3577976 . PMID   23220213.
  13. ↑ Hoffmann H, Schiene-Fischer C (Jul 2014). "Functional aspects of extracellular cyclophilins". Biological Chemistry. 395 (7–8): 721–35. doi:10.1515/hsz-2014-0125. PMID   24713575. S2CID   32395688.
  14. 1 2 3 McStay GP, Clarke SJ, Halestrap AP (Oct 2002). "Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore". The Biochemical Journal. 367 (Pt 2): 541–8. doi:10.1042/BJ20011672. PMC   1222909 . PMID   12149099.
  15. 1 2 Bowles KR, Zintz C, Abraham SE, Brandon L, Bowles NE, Towbin JA (Dec 1999). "Genomic characterization of the human peptidyl-prolyl-cis-trans-isomerase, mitochondrial precursor gene: assessment of its role in familial dilated cardiomyopathy". Human Genetics. 105 (6): 582–6. doi:10.1007/s004390051149. PMID   10647893.
  16. 1 2 He Y, Ge J, Tombran-Tink J (Nov 2008). "Mitochondrial defects and dysfunction in calcium regulation in glaucomatous trabecular meshwork cells". Investigative Ophthalmology & Visual Science. 49 (11): 4912–22. doi:10.1167/iovs.08-2192. PMID   18614807.

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