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4qib

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Revision as of 17:16, 4 January 2017

Oxidation-Mediated Inhibition of the Peptidyl-Prolyl Isomerase Pin1

Structural highlights

4qib is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:
Activity:	Peptidylprolyl isomerase, with EC number 5.2.1.8
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[PIN1_HUMAN] Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Pin1 is a phosphorylation-dependent peptidyl-prolyl isomerase that plays a critical role in mediating protein conformational changes involved in signaling processes related to cell cycle control. Pin1 has also been implicated as being neuroprotective in aging-related neurodegenerative disorders including Alzheimer's disease where Pin1 activity is diminished. Notably, recent proteomic analysis of brain samples from patients with mild cognitive impairment revealed that Pin1 is oxidized and also displays reduced activity. Since the Pin1 active site contains a functionally critical cysteine residue (Cys113) with a low predicted pKa, we hypothesized that Cys113 is sensitive to oxidation. Consistent with this hypothesis, we observed that treatment of Pin1 with hydrogen peroxide results in a 32Da mass increase, likely resulting from the oxidation of Cys113 to sulfinic acid (Cys-SO2H). This modification results in loss of peptidyl-prolyl isomerase activity. Notably, Pin1 with Cys113 substituted by aspartic acid retains activity and is no longer sensitive to oxidation. Structural studies by X-ray crystallography revealed increased electron density surrounding Cys113 following hydrogen peroxide treatment. At lower concentrations of hydrogen peroxide, oxidative inhibition of Pin1 can be partially reversed by treatment with dithiothreitol, suggesting that oxidation could be a reversible modification with a regulatory role. We conclude that the loss of Pin1 activity upon oxidation results from oxidative modification of the Cys113 sulfhydryl to sulfenic (Cys-SOH) or sulfinic acid (Cys-SO2H). Given the involvement of Pin1 in pathological processes related to neurodegenerative diseases and to cancer, these findings could have implications for the prevention or treatment of disease.

Peroxide-mediated oxidation and inhibition of the peptidyl-prolyl isomerase Pin1.,Innes BT, Sowole MA, Gyenis L, Dubinsky M, Konermann L, Litchfield DW, Brandl CJ, Shilton BH Biochim Biophys Acta. 2015 Jan 13. pii: S0925-4439(15)00014-9. doi:, 10.1016/j.bbadis.2014.12.025. PMID:25595659^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dougherty MK, Muller J, Ritt DA, Zhou M, Zhou XZ, Copeland TD, Conrads TP, Veenstra TD, Lu KP, Morrison DK. Regulation of Raf-1 by direct feedback phosphorylation. Mol Cell. 2005 Jan 21;17(2):215-24. PMID:15664191 doi:10.1016/j.molcel.2004.11.055
↑ Yu L, Mohamed AJ, Vargas L, Berglof A, Finn G, Lu KP, Smith CI. Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1. J Biol Chem. 2006 Jun 30;281(26):18201-7. Epub 2006 Apr 27. PMID:16644721 doi:10.1074/jbc.M603090200
↑ Lee TH, Chen CH, Suizu F, Huang P, Schiene-Fischer C, Daum S, Zhang YJ, Goate A, Chen RH, Zhou XZ, Lu KP. Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell. 2011 Apr 22;42(2):147-59. doi: 10.1016/j.molcel.2011.03.005. Epub 2011 , Apr 14. PMID:21497122 doi:10.1016/j.molcel.2011.03.005
↑ Innes BT, Sowole MA, Gyenis L, Dubinsky M, Konermann L, Litchfield DW, Brandl CJ, Shilton BH. Peroxide-mediated oxidation and inhibition of the peptidyl-prolyl isomerase Pin1. Biochim Biophys Acta. 2015 Jan 13. pii: S0925-4439(15)00014-9. doi:, 10.1016/j.bbadis.2014.12.025. PMID:25595659 doi:http://dx.doi.org/10.1016/j.bbadis.2014.12.025

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4qib"

@@ Line 1: / Line 1: @@
 ==Oxidation-Mediated Inhibition of the Peptidyl-Prolyl Isomerase Pin1==
 <StructureSection load='4qib' size='340' side='right' caption='[[4qib]], [[Resolution|resolution]] 1.86&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSD:3-SULFINOALANINE'>CSD</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qib OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4qib RCSB], [http://www.ebi.ac.uk/pdbsum/4qib PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4qib FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qib OCA], [http://pdbe.org/4qib PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qib RCSB], [http://www.ebi.ac.uk/pdbsum/4qib PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qib ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4qib" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Peptidyl-prolyl cis-trans isomerase|Peptidyl-prolyl cis-trans isomerase]]
 == References ==
 <references/>

4qib

From Proteopedia

Revision as of 17:16, 4 January 2017

Oxidation-Mediated Inhibition of the Peptidyl-Prolyl Isomerase Pin1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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