View source for 6cvp


==Human Aprataxin (Aptx) R199H bound to RNA-DNA, AMP and Zn product complex==
<StructureSection load='6cvp' size='340' side='right' caption='[[6cvp]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6cvp]] is a 6 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=6CVP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CVP FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AMP:ADENOSINE+MONOPHOSPHATE'>AMP</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ndf|4ndf]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">APTX, AXA1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6cvp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cvp OCA], [http://pdbe.org/6cvp PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cvp RCSB], [http://www.ebi.ac.uk/pdbsum/6cvp PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cvp ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/APTX_HUMAN APTX_HUMAN]] Defects in APTX are the cause of ataxia-oculomotor apraxia syndrome (AOA) [MIM:[http://omim.org/entry/208920 208920]]. AOA is an autosomal recessive syndrome characterized by early-onset cerebellar ataxia, oculomotor apraxia, early areflexia and late peripheral neuropathy.<ref>PMID:11586299</ref> <ref>PMID:11586300</ref> <ref>PMID:12196655</ref> <ref>PMID:12629250</ref> <ref>PMID:14506070</ref> <ref>PMID:15852392</ref> <ref>PMID:15699391</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/APTX_HUMAN APTX_HUMAN]] DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair and base excision repair. Resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species. Catalyzes the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. Also able to hydrolyze adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity.<ref>PMID:14755728</ref> <ref>PMID:15044383</ref> <ref>PMID:16547001</ref> <ref>PMID:16964241</ref> <ref>PMID:17276982</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The failure of DNA ligases to complete their catalytic reactions generates cytotoxic adenylated DNA strand breaks. The APTX RNA-DNA deadenylase protects genome integrity and corrects abortive DNA ligation arising during ribonucleotide excision repair and base excision DNA repair, and APTX human mutations cause the neurodegenerative disorder ataxia with oculomotor ataxia 1 (AOA1). How APTX senses cognate DNA nicks and is inactivated in AOA1 remains incompletely defined. Here, we report X-ray structures of APTX engaging nicked RNA-DNA substrates that provide direct evidence for a wedge-pivot-cut strategy for 5'-AMP resolution shared with the alternate 5'-AMP processing enzymes POLbeta and FEN1. Our results uncover a DNA-induced fit mechanism regulating APTX active site loop conformations and assembly of a catalytically competent active center. Further, based on comprehensive biochemical, X-ray and solution NMR results, we define a complex hierarchy for the differential impacts of the AOA1 mutational spectrum on APTX structure and activity. Sixteen AOA1 variants impact APTX protein stability, one mutation directly alters deadenylation reaction chemistry, and a dominant AOA1 variant unexpectedly allosterically modulates APTX active site conformations.

Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.,Tumbale P, Schellenberg MJ, Mueller GA, Fairweather E, Watson M, Little JN, Krahn J, Waddell I, London RE, Williams RS EMBO J. 2018 Jun 22. pii: embj.201798875. doi: 10.15252/embj.201798875. PMID:29934293<ref>PMID:29934293</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6cvp" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Schellenberg, M J]]
[[Category: Tumbale, P S]]
[[Category: Williams, R S]]
[[Category: 5'-dna end processing]]
[[Category: 5'-dna end recognition]]
[[Category: Dna repair]]
[[Category: Histidine triad domain]]
[[Category: Hit domain]]
[[Category: Hydrolase]]
[[Category: Hydrolase-dna-rna complex]]
[[Category: Protein-dna complex]]
[[Category: Zinc-finger]]