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[[Image:2rf5.jpg|left|200px]]


{{Structure
==Crystal structure of human tankyrase 1- catalytic PARP domain==
|PDB= 2rf5 |SIZE=350|CAPTION= <scene name='initialview01'>2rf5</scene>, resolution 2.30&Aring;
<StructureSection load='2rf5' size='340' side='right'caption='[[2rf5]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
|SITE= <scene name='pdbsite=AC1:Zn+Binding+Site+For+Residue+A+1'>AC1</scene> and <scene name='pdbsite=AC2:Gol+Binding+Site+For+Residue+A+1326'>AC2</scene>
== Structural highlights ==
|LIGAND= <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>
<table><tr><td colspan='2'>[[2rf5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RF5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2RF5 FirstGlance]. <br>
|ACTIVITY= [http://en.wikipedia.org/wiki/NAD(+)_ADP-ribosyltransferase NAD(+) ADP-ribosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.2.30 2.4.2.30]  
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
|GENE= TNKS, PARP5A, PARPL, TIN1, TINF1, TNKS1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
}}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2rf5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rf5 OCA], [https://pdbe.org/2rf5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2rf5 RCSB], [https://www.ebi.ac.uk/pdbsum/2rf5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2rf5 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/TNKS1_HUMAN TNKS1_HUMAN] Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.<ref>PMID:10988299</ref> <ref>PMID:11739745</ref> <ref>PMID:16076287</ref> <ref>PMID:19759537</ref> <ref>PMID:21478859</ref> <ref>PMID:22864114</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rf/2rf5_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2rf5 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Tankyrases are recently discovered proteins implicated in many important functions in the cell including telomere homeostasis and mitosis. Tankyrase modulates the activity of target proteins through poly(ADP-ribosyl)ation, and here we report the structure of the catalytic poly(ADP-ribose) polymerase (PARP) domain of human tankyrase 1. This is the first structure of a PARP domain from the tankyrase subfamily. The present structure reveals that tankyrases contain a short zinc-binding motif, which has not been predicted. Tankyrase activity contributes to telomere elongation observed in various cancer cells and tankyrase inhibition has been suggested as a potential route for cancer therapy. In comparison with other PARPs, significant structural differences are observed in the regions lining the substrate-binding site of tankyrase 1. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and tankyrase inhibitors, in particular.


'''Crystal structure of human tankyrase 1- catalytic PARP domain'''
Zinc binding catalytic domain of human tankyrase 1.,Lehtio L, Collins R, van den Berg S, Johansson A, Dahlgren LG, Hammarstrom M, Helleday T, Holmberg-Schiavone L, Karlberg T, Weigelt J J Mol Biol. 2008 May 23;379(1):136-45. Epub 2008 Apr 3. PMID:18436240<ref>PMID:18436240</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2rf5" style="background-color:#fffaf0;"></div>


==About this Structure==
==See Also==
2RF5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RF5 OCA].
*[[Poly(ADP-ribose) polymerase 3D structures|Poly(ADP-ribose) polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: NAD(+) ADP-ribosyltransferase]]
[[Category: Large Structures]]
[[Category: Single protein]]
[[Category: Arrowsmith CH]]
[[Category: Arrowsmith, C H.]]
[[Category: Berglund H]]
[[Category: Berg, S van den.]]
[[Category: Busam R]]
[[Category: Berglund, H.]]
[[Category: Collins R]]
[[Category: Busam, R.]]
[[Category: Dahlgren LG]]
[[Category: Collins, R.]]
[[Category: Edwards AM]]
[[Category: Dahlgren, L G.]]
[[Category: Flodin S]]
[[Category: Edwards, A M.]]
[[Category: Flores A]]
[[Category: Flodin, S.]]
[[Category: Graslund S]]
[[Category: Flores, A.]]
[[Category: Hammarstrom M]]
[[Category: Graslund, S.]]
[[Category: Herman MD]]
[[Category: Hammarstrom, M.]]
[[Category: Holmberg-Schiavone L]]
[[Category: Herman, M D.]]
[[Category: Johansson I]]
[[Category: Holmberg-Schiavone, L.]]
[[Category: Kallas A]]
[[Category: Johansson, I.]]
[[Category: Karlberg T]]
[[Category: Kallas, A.]]
[[Category: Kotenyova T]]
[[Category: Karlberg, T.]]
[[Category: Lehtio L]]
[[Category: Kotenyova, T.]]
[[Category: Moche M]]
[[Category: Lehtio, L.]]
[[Category: Nordlund P]]
[[Category: Moche, M.]]
[[Category: Nyman T]]
[[Category: Nordlund, P.]]
[[Category: Persson C]]
[[Category: Nyman, T.]]
[[Category: Sagemark J]]
[[Category: Persson, C.]]
[[Category: Sundstrom M]]
[[Category: SGC, Structural Genomics Consortium.]]
[[Category: Thorsell AG]]
[[Category: Sagemark, J.]]
[[Category: Tresaugues L]]
[[Category: Sundstrom, M.]]
[[Category: Weigelt J]]
[[Category: Thorsell, A G.]]
[[Category: Welin M]]
[[Category: Tresaugues, L.]]
[[Category: Van den Berg S]]
[[Category: Weigelt, J.]]
[[Category: Welin, M.]]
[[Category: GOL]]
[[Category: ZN]]
[[Category: adp-ribosylation]]
[[Category: alternative splicing]]
[[Category: ank repeat]]
[[Category: catalytic fragment]]
[[Category: chromosomal protein]]
[[Category: crystal structure]]
[[Category: cytoplasm]]
[[Category: glycosyltransferase]]
[[Category: golgi apparatus]]
[[Category: membrane]]
[[Category: mrna transport]]
[[Category: nad]]
[[Category: nuclear pore complex]]
[[Category: nucleus]]
[[Category: parp]]
[[Category: phosphorylation]]
[[Category: protein transport]]
[[Category: sgc]]
[[Category: structural genomic]]
[[Category: structural genomics consortium]]
[[Category: telomere]]
[[Category: transferase]]
[[Category: translocation]]
[[Category: transport]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 18:35:28 2008''

Latest revision as of 14:55, 30 August 2023

Crystal structure of human tankyrase 1- catalytic PARP domainCrystal structure of human tankyrase 1- catalytic PARP domain

Structural highlights

2rf5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

TNKS1_HUMAN Poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARsylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1.[1] [2] [3] [4] [5] [6]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Tankyrases are recently discovered proteins implicated in many important functions in the cell including telomere homeostasis and mitosis. Tankyrase modulates the activity of target proteins through poly(ADP-ribosyl)ation, and here we report the structure of the catalytic poly(ADP-ribose) polymerase (PARP) domain of human tankyrase 1. This is the first structure of a PARP domain from the tankyrase subfamily. The present structure reveals that tankyrases contain a short zinc-binding motif, which has not been predicted. Tankyrase activity contributes to telomere elongation observed in various cancer cells and tankyrase inhibition has been suggested as a potential route for cancer therapy. In comparison with other PARPs, significant structural differences are observed in the regions lining the substrate-binding site of tankyrase 1. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and tankyrase inhibitors, in particular.

Zinc binding catalytic domain of human tankyrase 1.,Lehtio L, Collins R, van den Berg S, Johansson A, Dahlgren LG, Hammarstrom M, Helleday T, Holmberg-Schiavone L, Karlberg T, Weigelt J J Mol Biol. 2008 May 23;379(1):136-45. Epub 2008 Apr 3. PMID:18436240[7]

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

See Also

References

  1. ↑ Chi NW, Lodish HF. Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles. J Biol Chem. 2000 Dec 8;275(49):38437-44. PMID:10988299 doi:10.1074/jbc.M007635200
  2. ↑ Cook BD, Dynek JN, Chang W, Shostak G, Smith S. Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol. 2002 Jan;22(1):332-42. PMID:11739745
  3. ↑ Chang W, Dynek JN, Smith S. NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis. Biochem J. 2005 Oct 15;391(Pt 2):177-84. PMID:16076287 doi:10.1042/BJ20050885
  4. ↑ Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009 Oct 1;461(7264):614-20. doi: 10.1038/nature08356. Epub 2009 Sep 16. PMID:19759537 doi:10.1038/nature08356
  5. ↑ Zhang Y, Liu S, Mickanin C, Feng Y, Charlat O, Michaud GA, Schirle M, Shi X, Hild M, Bauer A, Myer VE, Finan PM, Porter JA, Huang SM, Cong F. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol. 2011 May;13(5):623-9. doi: 10.1038/ncb2222. Epub 2011 Apr 10. PMID:21478859 doi:10.1038/ncb2222
  6. ↑ Ozaki Y, Matsui H, Asou H, Nagamachi A, Aki D, Honda H, Yasunaga S, Takihara Y, Yamamoto T, Izumi S, Ohsugi M, Inaba T. Poly-ADP ribosylation of Miki by tankyrase-1 promotes centrosome maturation. Mol Cell. 2012 Sep 14;47(5):694-706. doi: 10.1016/j.molcel.2012.06.033. Epub 2012, Aug 2. PMID:22864114 doi:10.1016/j.molcel.2012.06.033
  7. ↑ Lehtio L, Collins R, van den Berg S, Johansson A, Dahlgren LG, Hammarstrom M, Helleday T, Holmberg-Schiavone L, Karlberg T, Weigelt J. Zinc binding catalytic domain of human tankyrase 1. J Mol Biol. 2008 May 23;379(1):136-45. Epub 2008 Apr 3. PMID:18436240 doi:10.1016/j.jmb.2008.03.058

2rf5, resolution 2.30Å

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