PPIB

Last updated
PPIB
Protein PPIB PDB 1cyn.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PPIB , CYP-S1, CYPB, HEL-S-39, OI9, SCYLP, peptidylprolyl isomerase B, B
External IDs OMIM: 123841 MGI: 97750 HomoloGene: 726 GeneCards: PPIB
Orthologs
SpeciesHumanMouse
Entrez

5479

19035

Ensembl

ENSG00000166794

ENSMUSG00000032383

UniProt

P23284

P24369

RefSeq (mRNA)

NM_000942

NM_011149

RefSeq (protein)

NP_000933

NP_035279

Location (UCSC) Chr 15: 64.16 – 64.16 Mb Chr 9: 65.97 – 65.97 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. [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 regulate protein folding of type I collagen. [6] [7] Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.

Contents

Structure

Like other cyclophilins, PPIB 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. [8] In particular, PPIB is a 21 kDa protein which contains a C-terminal ER retention motif that directs the protein to the ER organelle, while its N-terminal extension attaches it to its substrates. [7] [9]

Function

PPIB is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds and regulate protein folding and maturation. Proline is the only amino acid known to exist in both the cis and trans isomerization rate in vivo, and is often the rate-limiting step in protein refolding. [10] The PPIase family is further divided into three structurally distinct subfamilies: cyclophilin (CyP), FK506-binding protein (FKBP), and parvulin (Pvn). [11] [12] While each family demonstrates PPIase activity, the families have no sequence of structural similarities. As a cyclophilin, PPIB binds cyclosporin A (CsA) and can be found within the cell or secreted by the cell. [9] [13]

Human PPIB

PPIB is the second of 18 cyclophilins to be identified in humans, after CypA. [11] [13] PPIB localizes to the endoplasmic reticulum (ER) and 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. [9] [14] It is also associated with viral infections. In eukaryotes, cyclophilins localize ubiquitously to many cell and tissue types. [9] [8] In addition to PPIase and protein chaperone activities, cyclophilins function in mitochondrial metabolism, apoptosis, immunological response, inflammation, and cell growth and proliferation. [6] [9] [8] Along with PPIC, PPIB localizes to the endoplasmic reticulum (ER), where it maintains redox homeostasis. Depletion of these two cyclophilins leads to hyperoxidation of the ER. [15]

In the ER, PPIB interacts with proteins such as P3H1, CRTAP, BiP, GRP94, PDI, and calreticulin to form foldase and chaperone complexes and facilitate protein folding, especially for type I collagen. [16] [17] This protein is the major PPIase for type I collagen, since the collagen contains an abundance of prolines that require cis-trans isomerization for proper folding. Thus, PPIB is essential for collagen biosynthesis and post-translational modification and affects fibril assembly, matrix cross-linking, and bone mineralization. [16]

In addition, it is associated with the secretory pathway and released in biological fluids. This protein can bind to cells derived from T- and B-lymphocytes, and may regulate cyclosporine A-mediated immunosuppression. [18] In one experiment, the addition of PPIB into cell cultures in vitro induced chemotaxis and integrin-mediated adhesion of T cells to the extracellular matrix (ECM), suggesting that it might function in innate immunity by recruiting T cells into infected tissue in vivo. [9]

Clinical significance

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

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. [9]

PPIB contributes to the replication and infection of viruses causing diseases such as AIDS, hepatitis C, measles, and influenza A. Thus, therapeutic targeting of PPIB with selective inhibitors may prove effective in combating viral infections and inflammation. [7] Currently, PPIB is employed as a biomarker for various types of cancer. [14] Moreover, there are two antigenic epitopes (CypB84-92 and CypB91-99) recognized by HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes which could be used as cancer vaccines, and in fact, were used to treat lung cancer in a clinical trial. [9]

Bacterial PPIB

PPIB has been identified in both Gram-negative bacteria and Gram-positive bacteria as an intracellular protein. In Escherichia coli , PPIB has been shown to have both PPIase activity and Chaperone (protein) activity. [19] In Staphylococcus aureus , PPIB has been shown to have PPIase activity, and to directly assist in the refolding of Staphylococcal nuclease. [20] Aside from these bacteria, PPIB has been identified in Brucella abortus, Mycobacterium tuberculosis , Bacillus subtilis and other bacteria. [21] [22] [23]

Interactions

PPIB 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.

In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. Immunophilins are traditionally classified into two families that differ in sequence and biochemical characteristics. These two families are: "cyclosporin-binding cyclophilins (CyPs)" and "FK506-binding proteins (FKBPs)". In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order.

<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">PDIA3</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase A3 (PDIA3), also known as glucose-regulated protein, 58-kD (GRP58), is an isomerase enzyme. This protein localizes to the endoplasmic reticulum (ER) and interacts with lectin chaperones calreticulin and calnexin (CNX) to modulate folding of newly synthesized glycoproteins. It is thought that complexes of lectins and this protein mediate protein folding by promoting formation of disulfide bonds in their glycoprotein substrates.

<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">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">P4HB</span> Protein-coding gene in the species Homo sapiens

Protein disulfide-isomerase, also known as the beta-subunit of prolyl 4-hydroxylase (P4HB), is an enzyme that in humans encoded by the P4HB gene. The human P4HB gene is localized in chromosome 17q25. Unlike other prolyl 4-hydroxylase family proteins, this protein is multifunctional and acts as an oxidoreductase for disulfide formation, breakage, and isomerization. The activity of P4HB is tightly regulated. Both dimer dissociation and substrate binding are likely to enhance its enzymatic activity during the catalysis process.

<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">PPIF</span> Protein-coding gene in the species Homo sapiens

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. 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. 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. In addition, PPIF participates in inflammation, as well as in ischemic reperfusion injury, AIDS, and cancer.

<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">FKBP10</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 10 is a protein that in humans is encoded by the FKBP10 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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000166794 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032383 - 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. ↑ Price ER, Zydowsky LD, Jin MJ, Baker CH, McKeon FD, Walsh CT (Apr 1991). "Human cyclophilin B: a second cyclophilin gene encodes a peptidyl-prolyl isomerase with a signal sequence". Proc Natl Acad Sci U S A. 88 (5): 1903–7. Bibcode:1991PNAS...88.1903P. doi: 10.1073/pnas.88.5.1903 . PMC   51134 . PMID   2000394.
  6. 1 2 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.
  7. 1 2 3 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.
  8. 1 2 3 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.
  9. 1 2 3 4 5 6 7 8 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. ↑ Göthel, S. F.; Marahiel, M. A. (March 1999). "Peptidyl-prolyl cis-trans isomerases, a superfamily of ubiquitous folding catalysts". Cellular and Molecular Life Sciences. 55 (3): 423–436. doi:10.1007/s000180050299. ISSN   1420-682X. PMID   10228556. S2CID   24868224.
  11. 1 2 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.
  12. ↑ 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.
  13. 1 2 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 Ray P, Rialon-Guevara KL, Veras E, Sullenger BA, White RR (May 2012). "Comparing human pancreatic cell secretomes by in vitro aptamer selection identifies cyclophilin B as a candidate pancreatic cancer biomarker". The Journal of Clinical Investigation. 122 (5): 1734–41. doi:10.1172/JCI62385. PMC   3336995 . PMID   22484812.
  15. ↑ 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.
  16. 1 2 3 4 5 6 Cabral WA, Perdivara I, Weis M, Terajima M, Blissett AR, Chang W, Perosky JE, Makareeva EN, Mertz EL, Leikin S, Tomer KB, Kozloff KM, Eyre DR, Yamauchi M, Marini JC (Jun 2014). "Abnormal type I collagen post-translational modification and crosslinking in a cyclophilin B KO mouse model of recessive osteogenesis imperfecta". PLOS Genetics. 10 (6): e1004465. doi: 10.1371/journal.pgen.1004465 . PMC   4072593 . PMID   24968150.
  17. 1 2 3 Ishikawa Y, Bächinger HP (Nov 2013). "An additional function of the rough endoplasmic reticulum protein complex prolyl 3-hydroxylase 1·cartilage-associated protein·cyclophilin B: the CXXXC motif reveals disulfide isomerase activity in vitro". The Journal of Biological Chemistry. 288 (44): 31437–46. doi: 10.1074/jbc.M113.498063 . PMC   3814740 . PMID   24043621.
  18. ↑ "Entrez Gene: PPIB peptidylprolyl isomerase B (cyclophilin B)".
  19. ↑ Skagia, Aggeliki; Vezyri, Eleni; Sigala, Markezina; Kokkinou, Areti; Karpusas, Michael; Venieraki, Anastasia; Katinakis, Panagiotis; Dimou, Maria (January 2017). "Structural and functional analysis of cyclophilin PpiB mutants supports an in vivo function not limited to prolyl isomerization activity". Genes to Cells: Devoted to Molecular & Cellular Mechanisms. 22 (1): 32–44. doi: 10.1111/gtc.12452 . ISSN   1365-2443. PMID   27868330.
  20. ↑ Wiemels, Richard E.; Cech, Stephanie M.; Meyer, Nikki M.; Burke, Caleb A.; Weiss, Andy; Parks, Anastacia R.; Shaw, Lindsey N.; Carroll, Ronan K. (2017-01-01). "An Intracellular Peptidyl-Prolyl cis/trans Isomerase Is Required for Folding and Activity of the Staphylococcus aureus Secreted Virulence Factor Nuclease". Journal of Bacteriology. 199 (1). doi:10.1128/JB.00453-16. ISSN   1098-5530. PMC   5165095 . PMID   27795319.
  21. ↑ Roset, Mara S.; García Fernández, Lucía; DelVecchio, Vito G.; Briones, Gabriel (February 2013). "Intracellularly Induced Cyclophilins Play an Important Role in Stress Adaptation and Virulence of Brucella abortus". Infection and Immunity. 81 (2): 521–530. doi:10.1128/IAI.01125-12. ISSN   0019-9567. PMC   3553818 . PMID   23230297.
  22. ↑ Göthel, S. F.; Scholz, C.; Schmid, F. X.; Marahiel, M. A. (1998-09-22). "Cyclophilin and trigger factor from Bacillus subtilis catalyze in vitro protein folding and are necessary for viability under starvation conditions". Biochemistry. 37 (38): 13392–13399. doi:10.1021/bi981253w. ISSN   0006-2960. PMID   9748346.
  23. ↑ Pandey, Saurabh; Sharma, Ashish; Tripathi, Deeksha; Kumar, Ashutosh; Khubaib, Mohd; Bhuwan, Manish; Chaudhuri, Tapan Kumar; Hasnain, Seyed Ehtesham; Ehtesham, Nasreen Zafar (2016-03-16). "Mycobacterium tuberculosis Peptidyl-Prolyl Isomerases Also Exhibit Chaperone like Activity In-Vitro and In-Vivo". PLOS ONE. 11 (3): e0150288. Bibcode:2016PLoSO..1150288P. doi: 10.1371/journal.pone.0150288 . ISSN   1932-6203. PMC   4794191 . PMID   26981873.
  24. ↑ Zhang J, Herscovitz H (Feb 2003). "Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B". J. Biol. Chem. 278 (9): 7459–68. doi: 10.1074/jbc.M207976200 . PMID   12397072.

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