6q00

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==TDP2 UBA Domain Bound to Ubiquitin at 0.85 Angstroms Resolution, Crystal Form 1==
==TDP2 UBA Domain Bound to Ubiquitin at 0.85 Angstroms Resolution, Crystal Form 1==
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<StructureSection load='6q00' size='340' side='right'caption='[[6q00]]' scene=''>
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<StructureSection load='6q00' size='340' side='right'caption='[[6q00]], [[Resolution|resolution]] 0.85&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q00 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Q00 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[6q00]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Q00 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Q00 FirstGlance]. <br>
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</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6q00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q00 OCA], [http://pdbe.org/6q00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q00 RCSB], [http://www.ebi.ac.uk/pdbsum/6q00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q00 ProSAT]</span></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">UBC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), TDP2, EAP2, TTRAP, AD-022 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6q00 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6q00 OCA], [http://pdbe.org/6q00 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6q00 RCSB], [http://www.ebi.ac.uk/pdbsum/6q00 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6q00 ProSAT]</span></td></tr>
</table>
</table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to TUD deficiency.
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== Function ==
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[[http://www.uniprot.org/uniprot/UBC_HUMAN UBC_HUMAN]] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.<ref>PMID:16543144</ref> <ref>PMID:19754430</ref> [[http://www.uniprot.org/uniprot/TYDP2_HUMAN TYDP2_HUMAN]] DNA repair enzyme that can remove a variety of covalent adducts from DNA through hydrolysis of a 5'-phosphodiester bond, giving rise to DNA with a free 5' phosphate. Catalyzes the hydrolysis of dead-end complexes between DNA and the topoisomerase 2 (TOP2) active site tyrosine residue. Hydrolyzes 5'-phosphoglycolates on protruding 5' ends on DNA double-strand breaks (DSBs) due to DNA damage by radiation and free radicals. The 5'-tyrosyl DNA phosphodiesterase activity can enable the repair of TOP2-induced DSBs without the need for nuclease activity, creating a 'clean' DSB with 5'-phosphate termini that are ready for ligation. Has preference for single-stranded DNA or duplex DNA with a 4 base pair overhang as substrate. Has also 3'-tyrosyl DNA phosphodiesterase activity, but less efficiently and much slower than TDP1. Constitutes the major if not only 5'-tyrosyl-DNA phosphodiesterase in cells. Also acts as a 5'-tyrosyl-RNA phosphodiesterase following picornavirus infection: its activity is hijacked by picornavirus and acts by specifically cleaving the protein-RNA covalent linkage generated during the viral genomic RNA replication steps of a picornavirus infection, without impairing the integrity of viral RNA. Also acts as an adapter by participating in the specific activation of MAP3K7/TAK1 in response to TGF-beta: associates with components of the TGF-beta receptor-TRAF6-TAK1 signaling module and promotes their ubiquitination dependent complex formation. Involved in non-canonical TGF-beta induced signaling routes. May also act as a negative regulator of ETS1 and may inhibit NF-kappa-B activation. Acts as a regulator of ribosome biogenesis following stress.<ref>PMID:19794497</ref> <ref>PMID:21030584</ref> <ref>PMID:21921940</ref> <ref>PMID:21980489</ref> <ref>PMID:22405347</ref> <ref>PMID:22822062</ref> <ref>PMID:22908287</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Tyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA-protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 functions is unknown. Here, we show that TDP2 co-purifies with K63 and K27 poly-Ubiquitinated cellular proteins independently of, and separately from SUMOylated TOP2 complexes. Poly-ubiquitin chains of &gt;/= Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA-protein crosslinks in vitro. X-ray crystal structures and small-angle X-ray scattering analysis of TDP2-Ub complexes reveal that the TDP2 UBA domain binds K63-Ub3 in a 1:1 stoichiometric complex that relieves a UBA-regulated autoinhibitory state of TDP2. Our data indicates that that poly-Ub regulates TDP2-catalyzed TOP2-DPC removal, and TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ubiquitin interface.
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Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2.,Schellenberg MJ, Appel CD, Riccio AA, Butler LR, Krahn JM, Liebermann JA, Cortes-Ledesma F, Williams RS Nucleic Acids Res. 2020 May 1. pii: 5827663. doi: 10.1093/nar/gkaa318. PMID:32356875<ref>PMID:32356875</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 6q00" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Krahn JM]]
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[[Category: Krahn, J M]]
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[[Category: Schellenberg MJ]]
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[[Category: Schellenberg, M J]]
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[[Category: Williams RS]]
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[[Category: Williams, R S]]
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[[Category: Cell signaling]]
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[[Category: Dna damage response]]
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[[Category: Post-translational modification]]
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[[Category: Signaling protein]]
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[[Category: Signaling protein-hydrolase complex]]
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[[Category: Tdp2]]
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[[Category: Topoisomerase 2]]

Current revision

TDP2 UBA Domain Bound to Ubiquitin at 0.85 Angstroms Resolution, Crystal Form 1

PDB ID 6q00

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