Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an
enzyme that in humans is encoded by the PIN1gene.[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
mitoticregulation. 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
cytokinemRNAs 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]
^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.
PMID31654518.
S2CID204907887.
^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.
PMID17876319.
^
abda 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.
PMID31654518.
S2CID204907887.
^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.
PMID30697729.
S2CID59412053.
^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.
PMID30684192.
S2CID59274466.
^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.
PMID10504341.
^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.
PMID12397362.
S2CID4311658.
^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.
PMID11575923.
Campbell HD, Webb GC, Fountain S, Young IG (Sep 1997). "The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31". Genomics. 44 (2): 157–62.
doi:
10.1006/geno.1997.4854.
PMID9299231.
Albert A, Lavoie S, Vincent M (Aug 1999). "A hyperphosphorylated form of RNA polymerase II is the major interphase antigen of the phosphoprotein antibody MPM-2 and interacts with the peptidyl-prolyl isomerase Pin1". Journal of Cell Science. 112. 112 (15): 2493–500.
doi:
10.1242/jcs.112.15.2493.
PMID10393805.
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. 112 (19): 3361–71.
doi:
10.1242/jcs.112.19.3361.
PMID10504341.
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.
Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an
enzyme that in humans is encoded by the PIN1gene.[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
mitoticregulation. 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
cytokinemRNAs 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]
^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.
PMID31654518.
S2CID204907887.
^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.
PMID17876319.
^
abda 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.
PMID31654518.
S2CID204907887.
^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.
PMID30697729.
S2CID59412053.
^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.
PMID30684192.
S2CID59274466.
^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.
PMID10504341.
^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.
PMID12397362.
S2CID4311658.
^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.
PMID11575923.
Campbell HD, Webb GC, Fountain S, Young IG (Sep 1997). "The human PIN1 peptidyl-prolyl cis/trans isomerase gene maps to human chromosome 19p13 and the closely related PIN1L gene to 1p31". Genomics. 44 (2): 157–62.
doi:
10.1006/geno.1997.4854.
PMID9299231.
Albert A, Lavoie S, Vincent M (Aug 1999). "A hyperphosphorylated form of RNA polymerase II is the major interphase antigen of the phosphoprotein antibody MPM-2 and interacts with the peptidyl-prolyl isomerase Pin1". Journal of Cell Science. 112. 112 (15): 2493–500.
doi:
10.1242/jcs.112.15.2493.
PMID10393805.
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. 112 (19): 3361–71.
doi:
10.1242/jcs.112.19.3361.
PMID10504341.
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.