Structure of an aprataxin-DNA complex with insights into AOA1 neurodegenerative disease

Percy Tumbale, C. Denise Appel, Rolf Kraehenbuehl, Patrick D. Robertson, Jessica S. Williams, Joe Krahn, Ivan Ahel, R. Scott Williams

Research output: Contribution to journalArticlepeer-review

Abstract

DNA 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). © 2011 Nature America, Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1189-1195
Number of pages6
JournalNature Structural and Molecular Biology
Volume18
Issue number11
DOIs
Publication statusPublished - Nov 2011

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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