Biology:PIN1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.[1][2]

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[3][4] and immune disorders.[5]

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).[6] 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.[7]

Inhibition

PIN1 has been widely investigated as an interesting molecular target for the inhibition of cancer cell lines,[8][9] such as breast, cervical, ovarian, and endometrial cancers.[10] Studies have demonstrated that all-trans retinoic acid (ATRA), a natural compound derivative from Vitamin A is involved with PIN1 inhibition.[11] Furthermore, ATRA has also been reported to synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit cancer growth.[12] Some elemonic acid derivatives have also been reported with inhibitory activity against PIN1.[13] Some computational evidence has also demonstrated that some triterpenoids from neem could also inhibit PIN1 in a similar manner to elemonic acid derivatives[8]

Interactions

PIN1 has been shown to interact with:


References

  1. ↑ "A human peptidyl-prolyl isomerase essential for regulation of mitosis". Nature 380 (6574): 544–7. Apr 1996. doi:10.1038/380544a0. PMID 8606777. 
  2. ↑ "Entrez Gene: PIN1 Protein (peptidylprolyl cis/trans isomerase) NIMA-interacting 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5300. 
  3. ↑ da Costa, Kauê Santana; Galúcio, João Marcos; de Jesus, Deivid Almeida; Gomes, Guelber Cardoso; Lima e Lima, Anderson Henrique; Taube, Paulo Sérgio; dos Santos, Alberto Monteiro; Lameira, Jerônimo (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. 
  4. ↑ Campaner, Elena; Rustighi, Alessandra; Zannini, Alessandro; Cristiani, Alberto; Piazza, Silvano; Ciani, Yari; Kalid, Ori; Golan, Gali et al. (August 2017). "A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action". Nature Communications 8 (1): 15772. doi:10.1038/ncomms15772. ISSN 2041-1723. PMID 28598431. 
  5. ↑ Rudrabhatla, P.; Albers, W.; Pant, H. C. (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. PMID 19940183. 
  6. ↑ "Nuclear import of Pin1 is mediated by a novel sequence in the PPIase domain". FEBS Letters 583 (2): 271–276. 2009. doi:10.1016/j.febslet.2008.12.011. PMID 19084525. 
  7. ↑ "Prolyl cis-trans isomerization as a molecular timer". Nature Chemical Biology 3 (10): 619–29. Oct 2007. doi:10.1038/nchembio.2007.35. PMID 17876319. 
  8. ↑ 8.0 8.1 "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. 2020-11-09. doi:10.2174/1573409915666191025114009. PMID 31654518. 
  9. ↑ "Virtual screening identifies a PIN1 inhibitor with possible antiovarian cancer effects". Journal of Cellular Physiology 234 (9): 15708–15716. January 2019. doi:10.1002/jcp.28224. PMID 30697729. 
  10. ↑ "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. February 2019. doi:10.1007/s12272-019-01122-3. PMID 30684192. 
  11. ↑ "Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer". Nature Medicine 21 (5): 457–66. May 2015. doi:10.1038/nm.3839. PMID 25849135. 
  12. ↑ "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. May 2017. doi:10.18632/oncotarget.15967. PMID 28404959. 
  13. ↑ "Synthesis of the novel elemonic acid derivatives as Pin1 inhibitors". Bioorganic & Medicinal Chemistry Letters 24 (24): 5612–5615. December 2014. doi:10.1016/j.bmcl.2014.10.087. PMID 25466185. 
  14. ↑ "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. Jul 2001. doi:10.1093/emboj/20.13.3459. PMID 11432833. 
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins". Genes & Development 12 (5): 706–20. Mar 1998. doi:10.1101/gad.12.5.706. PMID 9499405. 
  16. ↑ "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. Nov 2001. doi:10.1128/MCB.21.22.7617-7628.2001. PMID 11604498. 
  17. ↑ 17.0 17.1 17.2 "Function of WW domains as phosphoserine- or phosphothreonine-binding modules". Science 283 (5406): 1325–8. Feb 1999. doi:10.1126/science.283.5406.1325. PMID 10037602. Bibcode: 1999Sci...283.1325L. 
  18. ↑ 18.0 18.1 "Interactions between protein kinase CK2 and Pin1. Evidence for phosphorylation-dependent interactions". The Journal of Biological Chemistry 277 (25): 23054–64. Jun 2002. doi:10.1074/jbc.M200111200. PMID 11940573. 
  19. ↑ "Cell cycle-dependent phosphorylation of Disabled-2 by cdc2". Oncogene 22 (29): 4524–30. Jul 2003. doi:10.1038/sj.onc.1206767. PMID 12881709. 
  20. ↑ "Pin1 prolyl isomerase regulates endothelial nitric oxide synthase". Arteriosclerosis, Thrombosis, and Vascular Biology 31 (2): 392–8. Feb 2011. doi:10.1161/ATVBAHA.110.213181. PMID 21051667. 
  21. ↑ "The peptidyl-isomerase Pin1 regulates p27kip1 expression through inhibition of Forkhead box O tumor suppressors". Cancer Research 68 (18): 7597–605. Sep 2008. doi:10.1158/0008-5472.CAN-08-1059. PMID 18794148. 
  22. ↑ "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. Oct 2001. doi:10.1074/jbc.M106207200. PMID 11470801. 
  23. ↑ "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. Oct 1999. doi:10.1242/jcs.112.19.3361. PMID 10504341. 
  24. ↑ 24.0 24.1 "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. Mar 2009. doi:10.1074/jbc.M804659200. PMID 19122240. 
  25. ↑ "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. Dec 2002. doi:10.1074/jbc.C200538200. PMID 12388558. 
  26. ↑ "The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults". Nature 419 (6909): 853–7. Oct 2002. doi:10.1038/nature01120. PMID 12397362. 
  27. ↑ "The peptidyl-prolyl isomerase Pin1 interacts with hSpt5 phosphorylated by Cdk9". Journal of Molecular Biology 312 (4): 675–85. Sep 2001. doi:10.1006/jmbi.2001.4991. PMID 11575923. 
  28. ↑ "Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance". Nature Cell Biology 11 (1): 97–105. 2009. doi:10.1038/ncb1818. PMID 19060891. 

Further reading

External links

  • Overview of all the structural information available in the PDB for UniProt: Q13526 (Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) at the PDBe-KB.



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