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dc.contributor.authorTumbale, P
dc.contributor.authorAppel, C
dc.contributor.authorKraehenbuehl, Rolf
dc.contributor.authorRobertson, P
dc.contributor.authorWilliams, J
dc.contributor.authorKrahn, J
dc.contributor.authorAhel, Ivan
dc.contributor.authorWilliams, R
dc.date.accessioned2012-03-01T13:34:56Z
dc.date.available2012-03-01T13:34:56Z
dc.date.issued2011-11
dc.identifier.citationStructure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease. 2011, 18 (11):1189-95 Nat Struct Mol Biolen
dc.identifier.issn1545-9985
dc.identifier.pmid21984210
dc.identifier.doi10.1038/nsmb.2146
dc.identifier.urihttp://hdl.handle.net/10541/213729
dc.description.abstractDNA ligases finalize DNA replication and repair through DNA nick-sealing reactions that can abort to generate cytotoxic 5'-adenylation DNA damage. Aprataxin (Aptx) catalyzes direct reversal of 5'-adenylate adducts to protect genome integrity. Here the structure of a Schizosaccharomyces pombe Aptx-DNA-AMP-Zn(2+) complex reveals active site and DNA interaction clefts formed by fusing a histidine triad (HIT) nucleotide hydrolase with a DNA minor groove-binding C(2)HE zinc finger (Znf). An Aptx helical 'wedge' interrogates the base stack for sensing DNA ends or DNA nicks. The HIT-Znf, the wedge and an '[F/Y]PK' pivot motif cooperate to distort terminal DNA base-pairing and direct 5'-adenylate into the active site pocket. Structural and mutational data support a wedge-pivot-cut HIT-Znf catalytic mechanism for 5'-adenylate adduct recognition and removal and suggest that mutations affecting protein folding, the active site pocket and the pivot motif underlie Aptx dysfunction in the neurodegenerative disorder ataxia with oculomotor apraxia 1 (AOA1).
dc.language.isoenen
dc.subject.meshAmino Acid Motifs
dc.subject.meshApraxias
dc.subject.meshAtaxia Telangiectasia
dc.subject.meshBinding Sites
dc.subject.meshCrystallography, X-Ray
dc.subject.meshDNA
dc.subject.meshDNA Breaks, Single-Stranded
dc.subject.meshDNA Damage
dc.subject.meshDNA Repair
dc.subject.meshDNA-Binding Proteins
dc.subject.meshHumans
dc.subject.meshHypoalbuminemia
dc.subject.meshModels, Molecular
dc.subject.meshMolecular Sequence Data
dc.subject.meshMutation
dc.subject.meshNuclear Proteins
dc.subject.meshNucleic Acid Conformation
dc.subject.meshProtein Structure, Tertiary
dc.subject.meshZinc Fingers
dc.titleStructure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease.en
dc.typeArticleen
dc.contributor.departmentLaboratory of Structural Biology, National Institute of Environmental Health Sciences, US National Institutes of Health, Department of Health and Human Services, North Carolina, USA.en
dc.identifier.journalNature Structural & Molecular Biologyen
html.description.abstractDNA ligases finalize DNA replication and repair through DNA nick-sealing reactions that can abort to generate cytotoxic 5'-adenylation DNA damage. Aprataxin (Aptx) catalyzes direct reversal of 5'-adenylate adducts to protect genome integrity. Here the structure of a Schizosaccharomyces pombe Aptx-DNA-AMP-Zn(2+) complex reveals active site and DNA interaction clefts formed by fusing a histidine triad (HIT) nucleotide hydrolase with a DNA minor groove-binding C(2)HE zinc finger (Znf). An Aptx helical 'wedge' interrogates the base stack for sensing DNA ends or DNA nicks. The HIT-Znf, the wedge and an '[F/Y]PK' pivot motif cooperate to distort terminal DNA base-pairing and direct 5'-adenylate into the active site pocket. Structural and mutational data support a wedge-pivot-cut HIT-Znf catalytic mechanism for 5'-adenylate adduct recognition and removal and suggest that mutations affecting protein folding, the active site pocket and the pivot motif underlie Aptx dysfunction in the neurodegenerative disorder ataxia with oculomotor apraxia 1 (AOA1).


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