PIN1

Peptidylprolyl cis/trans isomerase, NIMA-interacting 1
PDB rendering based on 1f8a.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1F8A, 1I6C, 1I8G, 1I8H, 1NMV, 1NMW, 1PIN, 1ZCN, 2F21, 2ITK, 2KBU, 2KCF, 2LB3, 2M8I, 2M8J, 2M9E, 2M9F, 2M9I, 2M9J, 2Q5A, 2XP3, 2XP4, 2XP5, 2XP6, 2XP7, 2XP8, 2XP9, 2XPA, 2XPB, 2ZQS, 2ZQT, 2ZQU, 2ZQV, 2ZR4, 2ZR5, 2ZR6, 3I6C, 3IK8, 3IKD, 3IKG, 3JYJ, 3KAB, 3KAC, 3KAD, 3KAF, 3KAG, 3KAH, 3KAI, 3KCE, 3NTP, 3ODK, 3OOB, 3TC5, 3TCZ, 3TDB, 4GWT, 4GWV
Identifiers
Symbols	PIN1 ; DOD; UBL5
External IDs	OMIM: 601052 MGI: 1346036 HomoloGene: 4531 ChEMBL: 2288 GeneCards: PIN1 Gene
EC number	5.2.1.8
Gene ontology Molecular function • peptidyl-prolyl cis-trans isomerase activity • protein binding • mitogen-activated protein kinase kinase binding • GTPase activating protein binding • phosphoserine binding • phosphothreonine binding Cellular component • nucleus • nucleoplasm • cytoplasm • nuclear speck • midbody Biological process • protein peptidyl-prolyl isomerization • positive regulation of protein phosphorylation • protein folding • cell cycle • regulation of mitosis • cytokine-mediated signaling pathway • negative regulation of transforming growth factor beta receptor signaling pathway • positive regulation of Rho GTPase activity • regulation of cytokinesis • negative regulation of type I interferon production • innate immune response • positive regulation of ubiquitin-protein transferase activity • regulation of pathway-restricted SMAD protein phosphorylation • negative regulation of ERK1 and ERK2 cascade • negative regulation of cell motility Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5300	23988
Ensembl	ENSG00000127445	ENSMUSG00000032171
UniProt	Q13526	Q9QUR7
RefSeq (mRNA)	NM_006221	NM_023371
RefSeq (protein)	NP_006212	NP_075860
Location (UCSC)	Chr 19: 9.95 – 9.96 Mb	Chr 9: 20.65 – 20.67 Mb
PubMed search

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.^[1][2] (Not to be confused with PIN1 (Pin-formed 1), an auxin transporter in Arabidopsis thaliana.)

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 may be implicated in certain cancers, and the down-regulation of Pin1 may be implicated in Alzheimer's disease. Inhibitors of Pin1 may have therapeutic implications for cancer and immune disorders.

Discovery and characterization

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 of Pin1

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. 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.

Biological 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. A recent review by Kun Ping Lu attempts to provide a unifying framework for understanding Pin1 function by hypothesising that Pin1 acts as a molecular timer.^[3]

Interactions

PIN1 has been shown to interact with CSNK2A2,^[4] Casein kinase 2, alpha 1,^[4] Wee1-like protein kinase,^[5] FOXO4,^[6] CDC25C,^[5][7][8] CDC27,^[5][8] MYT1,^[9] PLK1,^[5][8] MPHOSPH1,^[10] DAB2,^[11] P53,^[12][13] PKMYT1,^[5] C-jun,^[14] SUPT5H,^[15] Mothers against decapentaplegic homolog 3^[16] and Mothers against decapentaplegic homolog 2.^[16] PIN1 has also been shown to interact with endothelial nitric oxide synthase (eNOS).^[17]

References

Further reading

PDB gallery 1f8a: STRUCTURAL BASIS FOR THE PHOSPHOSERINE-PROLINE RECOGNITION BY GROUP IV WW DOMAINS  1i6c: SOLUTION STRUCTURE OF PIN1 WW DOMAIN  1i8g: SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH CDC25 PHOSPHOTHREONINE PEPTIDE  1i8h: SOLUTION STRUCTURE OF PIN1 WW DOMAIN COMPLEXED WITH HUMAN TAU PHOSPHOTHREONINE PEPTIDE  1nmv: Solution structure of human Pin1  1nmw: Solution structure of the PPIase domain of human Pin1  1pin: PIN1 PEPTIDYL-PROLYL CIS-TRANS ISOMERASE FROM HOMO SAPIENS  1zcn: human Pin1 Ng mutant  2f21: human Pin1 Fip mutant  2itk: human Pin1 bound to D-PEPTIDE