PIN1

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PIN1
Protein PIN1 PDB 1f8a.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PIN1 , DOD, UBL5, peptidylprolyl cis/trans isomerase, NIMA-interacting 1
External IDs OMIM: 601052 MGI: 1346036 HomoloGene: 4531 GeneCards: PIN1
Orthologs
SpeciesHumanMouse
Entrez

5300

23988

Ensembl

ENSG00000127445

ENSMUSG00000032171

UniProt

Q13526

Q9QUR7

RefSeq (mRNA)

NM_006221

NM_023371
NM_001364495

RefSeq (protein)

NP_006212

NP_075860
NP_001351424

Location (UCSC) Chr 19: 9.84 – 9.85 Mb Chr 9: 20.56 – 20.58 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene. [5] [6]

Pin 1, or peptidyl-prolyl cis/trans isomerase (PPIase), isomerizes only phospho-Serine/Threonine-Proline motifs. The enzyme binds to a subset of proteins and thus plays a role as a post phosphorylation control in regulating protein function. Studies have shown that the deregulation of Pin1 may play a pivotal role in various diseases. Notably, the up-regulation of Pin1 is implicated in certain cancers, and the down-regulation of Pin1 is implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer [7] [8] and immune disorders. [9]

Discovery

The gene encoding Pin1 was identified in 1996 as a result of a genetic/biochemical screen for proteins involved in mitotic regulation. It was found to be essential for cell division in some organisms. By 1999, however, it was apparent that Pin1 knockout mice had a surprisingly mild phenotype, indicating that the enzyme was not required for cell division per se. Further studies later found that loss of Pin1 in mice displays are not only neuronal degenerative phenotypes but also several abnormalities, similar to those of cyclin D1-null mice, suggesting the conformation changes mediated by Pin1 may be crucial for cell normal function.

Activation

Phosphorylation of Ser/Thr-Pro motifs in substrates is required for recognition by Pin1. Pin is a small protein at 18 kDa and does not have a nuclear localization or export signal. However, 2009, Lufei et al. reported that Pin1 has putative novel nuclear localization signal (NLS) and Pin1 interacts with importin α5 (KPNA1). [10] Substrate interactions and a WW domain determine subcellular distribution. Expression is induced by growth signals from E2F transcription factors. Expression levels fluctuate in normal, but not in cancerous cells. Expression is often associated with cell proliferation. Postranslational modifications such as phosphorylation on Ser16 inhibit the ability of Pin1 to bind substrate, and this inhibitory process may be altered during oncogenesis. It is hypothesized, but not proven, that Pin1 might also be regulated by proteolytic pathways.

Function

Pin1 activity regulates the outcome of proline-directed kinase (e.g. MAPK, CDK or GSK3) signalling and consequently regulates cell proliferation (in part through control of cyclin D1 levels and stability) and cell survival. The precise effects of Pin1 depend upon the system: Pin1 accelerates dephosphorylation of Cdc25 and Tau, but protects phosphorylated cyclin D from ubiquitination and proteolysis. Recent data also implicate Pin1 as playing an important role in immune responses, at least in part by increasing the stability of cytokine mRNAs by influencing the protein complexes to which they bind. Pin1 has been hypothesized to act as a molecular timer. [11]

Inhibition

PIN1 has been widely investigated as an interesting molecular target for the inhibition of cancer cell lines, [12] [13] such as breast, cervical, ovarian, and endometrial cancers. [14] Studies have demonstrated that all-trans retinoic acid (ATRA), a natural compound derivative from Vitamin A is involved with PIN1 inhibition. [15] Furthermore, ATRA has also been reported to synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit cancer growth. [16] Some elemonic acid derivatives have also been reported with inhibitory activity against PIN1. [17] Some computational evidence has also demonstrated that some triterpenoids from neem could also inhibit PIN1 in a similar manner to elemonic acid derivatives [12]

Interactions

PIN1 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">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">Cyclin-dependent kinase 1</span> Mammalian protein found in Homo sapiens

Cyclin-dependent kinase 1 also known as CDK1 or cell division cycle protein 2 homolog is a highly conserved protein that functions as a serine/threonine protein kinase, and is a key player in cell cycle regulation. It has been highly studied in the budding yeast S. cerevisiae, and the fission yeast S. pombe, where it is encoded by genes cdc28 and cdc2, respectively. With its cyclin partners, Cdk1 forms complexes that phosphorylate a variety of target substrates ; phosphorylation of these proteins leads to cell cycle progression.

<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">PLK1</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PLK1, also known as polo-like kinase 1 (PLK-1) or serine/threonine-protein kinase 13 (STPK13), is an enzyme that in humans is encoded by the PLK1 gene.

<span class="mw-page-title-main">Wee1-like protein kinase</span> Protein-coding gene in the species Homo sapiens

WEE1 homolog , also known as WEE1, is a protein which in humans is encoded by the WEE1 gene.

<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">CDC25C</span> Protein-coding gene in the species Homo sapiens

M-phase inducer phosphatase 3 is an enzyme that in humans is encoded by the CDC25C gene.

<span class="mw-page-title-main">Telomeric repeat-binding factor 1</span> Protein-coding gene in humans

Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in the species Homo sapiens

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 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">PKMYT1</span> Protein-coding gene in the species Homo sapiens

Membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase also known as Myt1 kinase is an enzyme that in humans is encoded by the PKMYT1 gene.

<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">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">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">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.

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: ENSG00000127445 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032171 - 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. ↑ Lu KP, Hanes SD, Hunter T (Apr 1996). "A human peptidyl-prolyl isomerase essential for regulation of mitosis". Nature. 380 (6574): 544–7. Bibcode:1996Natur.380..544P. doi:10.1038/380544a0. PMID   8606777. S2CID   4258406.
  6. ↑ "Entrez Gene: PIN1 Protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1".
  7. ↑ da Costa KS, Galúcio JM, de Jesus DA, Gomes GC, Lima e Lima AH, Taube PS, dos Santos AM, Lameira J (2019-10-25). "Targeting Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors". Current Computer-Aided Drug Design. 15 (5): 605–617. doi:10.2174/1573409915666191025114009. PMID   31654518. S2CID   204907887.
  8. ↑ Campaner E, Rustighi A, Zannini A, Cristiani A, Piazza S, Ciani Y, Kalid O, Golan G, Baloglu E, Shacham S, Valsasina B (August 2017). "A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action". Nature Communications. 8 (1): 15772. Bibcode:2017NatCo...815772C. doi:10.1038/ncomms15772. ISSN   2041-1723. PMC   5472749 . PMID   28598431.
  9. ↑ Rudrabhatla P, Albers W, Pant HC (2009-11-25). "Peptidyl-Prolyl Isomerase 1 Regulates Protein Phosphatase 2A-Mediated Topographic Phosphorylation of Neurofilament Proteins". Journal of Neuroscience. 29 (47): 14869–14880. doi:10.1523/JNEUROSCI.4469-09.2009. ISSN   0270-6474. PMC   3849796 . PMID   19940183.
  10. ↑ Lufei C, Cao X (2009). "Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain". FEBS Letters. 583 (2): 271–276. doi:10.1016/j.febslet.2008.12.011. PMID   19084525. S2CID   23995242.
  11. ↑ Lu KP, Finn G, Lee TH, Nicholson LK (Oct 2007). "Prolyl cis-trans isomerization as a molecular timer". Nature Chemical Biology. 3 (10): 619–29. doi:10.1038/nchembio.2007.35. PMID   17876319.
  12. 1 2 da Costa KS, Galúcio JM, de Jesus DA, Gomes GC, Lima E, Lima AH, et al. (2020-11-09). "Targeting Peptidyl-prolyl Cis-trans Isomerase NIMA-interacting 1: A Structure-based Virtual Screening Approach to Find Novel Inhibitors". Current Computer-Aided Drug Design. 16 (5): 605–617. doi:10.2174/1573409915666191025114009. PMID   31654518. S2CID   204907887.
  13. ↑ Russo Spena C, De Stefano L, Poli G, Granchi C, El Boustani M, Ecca F, et al. (January 2019). "Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects". Journal of Cellular Physiology. 234 (9): 15708–15716. doi:10.1002/jcp.28224. hdl: 10278/3711934 . PMID   30697729. S2CID   59412053.
  14. ↑ Kim G, Bhattarai PY, Choi HS (February 2019). "Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 as a molecular target in breast cancer: a therapeutic perspective of gynecological cancer". Archives of Pharmacal Research. 42 (2): 128–139. doi:10.1007/s12272-019-01122-3. PMID   30684192. S2CID   59274466.
  15. ↑ Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, et al. (May 2015). "Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer". Nature Medicine. 21 (5): 457–66. doi:10.1038/nm.3839. PMC   4425616 . PMID   25849135.
  16. ↑ Zheng M, Xu H, Liao XH, Chen CP, Zhang AL, Lu W, et al. (May 2017). "Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma". Oncotarget. 8 (18): 29771–29784. doi:10.18632/oncotarget.15967. PMC   5444702 . PMID   28404959.
  17. ↑ Li X, Li L, Zhou Q, Zhang N, Zhang S, Zhao R, et al. (December 2014). "Synthesis of the novel elemonic acid derivatives as Pin1 inhibitors". Bioorganic & Medicinal Chemistry Letters. 24 (24): 5612–5615. doi:10.1016/j.bmcl.2014.10.087. PMID   25466185.
  18. ↑ Wulf GM, Ryo A, Wulf GG, Lee SW, Niu T, Petkova V, Lu KP (Jul 2001). "Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1". The EMBO Journal. 20 (13): 3459–72. doi:10.1093/emboj/20.13.3459. PMC   125530 . PMID   11432833.
  19. 1 2 3 4 5 Shen M, Stukenberg PT, Kirschner MW, Lu KP (Mar 1998). "The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins". Genes & Development. 12 (5): 706–20. doi:10.1101/gad.12.5.706. PMC   316589 . PMID   9499405.
  20. ↑ Goldstrohm AC, Albrecht TR, Suñé C, Bedford MT, Garcia-Blanco MA (Nov 2001). "The transcription elongation factor CA150 interacts with RNA polymerase II and the pre-mRNA splicing factor SF1". Molecular and Cellular Biology. 21 (22): 7617–28. doi:10.1128/MCB.21.22.7617-7628.2001. PMC   99933 . PMID   11604498.
  21. 1 2 3 Lu PJ, Zhou XZ, Shen M, Lu KP (Feb 1999). "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science. 283 (5406): 1325–8. Bibcode:1999Sci...283.1325L. doi:10.1126/science.283.5406.1325. PMID   10037602.
  22. 1 2 Messenger MM, Saulnier RB, Gilchrist AD, Diamond P, Gorbsky GJ, Litchfield DW (Jun 2002). "Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions". The Journal of Biological Chemistry. 277 (25): 23054–64. doi: 10.1074/jbc.M200111200 . PMID   11940573.
  23. ↑ He J, Xu J, Xu XX, Hall RA (Jul 2003). "Cell cycle-dependent phosphorylation of Disabled-2 by cdc2". Oncogene. 22 (29): 4524–30. doi:10.1038/sj.onc.1206767. PMID   12881709. S2CID   1086352.
  24. ↑ Ruan L, Torres CM, Qian J, Chen F, Mintz JD, Stepp DW, Fulton D, Venema RC (Feb 2011). "Pin1 prolyl isomerase regulates endothelial nitric oxide synthase". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (2): 392–8. doi:10.1161/ATVBAHA.110.213181. PMC   3075952 . PMID   21051667.
  25. ↑ Brenkman AB, de Keizer PL, van den Broek NJ, van der Groep P, van Diest PJ, van der Horst A, Smits AM, Burgering BM (Sep 2008). "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Research. 68 (18): 7597–605. doi: 10.1158/0008-5472.CAN-08-1059 . PMID   18794148.
  26. ↑ Kamimoto T, Zama T, Aoki R, Muro Y, Hagiwara M (Oct 2001). "Identification of a novel kinesin-related protein, KRMP1, as a target for mitotic peptidyl-prolyl isomerase Pin1". The Journal of Biological Chemistry. 276 (40): 37520–8. doi: 10.1074/jbc.M106207200 . PMID   11470801.
  27. ↑ Wells NJ, Watanabe N, Tokusumi T, Jiang W, Verdecia MA, Hunter T (Oct 1999). "The C-terminal domain of the Cdc2 inhibitory kinase Myt1 interacts with Cdc2 complexes and is required for inhibition of G(2)/M progression". Journal of Cell Science. 112 (19): 3361–71. doi:10.1242/jcs.112.19.3361. PMID   10504341.
  28. 1 2 Nakano A, Koinuma D, Miyazawa K, Uchida T, Saitoh M, Kawabata M, Hanai J, Akiyama H, Abe M, Miyazono K, Matsumoto T, Imamura T (Mar 2009). "Pin1 down-regulates transforming growth factor-beta (TGF-beta) signaling by inducing degradation of Smad proteins". The Journal of Biological Chemistry. 284 (10): 6109–15. doi: 10.1074/jbc.M804659200 . PMID   19122240.
  29. ↑ Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP (Dec 2002). "Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage". The Journal of Biological Chemistry. 277 (50): 47976–9. doi: 10.1074/jbc.C200538200 . PMID   12388558.
  30. ↑ Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S, Ronai Z, Blandino G, Schneider C, Del Sal G (Oct 2002). "The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults". Nature. 419 (6909): 853–7. Bibcode:2002Natur.419..853Z. doi:10.1038/nature01120. PMID   12397362. S2CID   4311658.
  31. ↑ Lavoie SB, Albert AL, Handa H, Vincent M, Bensaude O (Sep 2001). "The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9". Journal of Molecular Biology. 312 (4): 675–85. doi:10.1006/jmbi.2001.4991. PMID   11575923.
  32. ↑ Lee TH, Tun-Kyi A, Shi R, Lim J, Soohoo C, Finn G, Balastik M, Pastorino L, Wulf G, Zhou XZ, Lu KP (2009). "Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance". Nature Cell Biology. 11 (1): 97–105. doi:10.1038/ncb1818. PMC   2699942 . PMID   19060891.

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