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

Nat Struct Mol Biol. 2011 Oct 9;18(11):1189-95. doi: 10.1038/nsmb.2146.

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).

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Motifs
  • Apraxias / genetics*
  • Apraxias / physiopathology*
  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / physiopathology*
  • Binding Sites
  • Cerebellar Ataxia / congenital
  • Crystallography, X-Ray
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • DNA Breaks, Single-Stranded
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Hypoalbuminemia / genetics*
  • Hypoalbuminemia / physiopathology*
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nucleic Acid Conformation
  • Protein Structure, Tertiary
  • Zinc Fingers

Substances

  • APTX protein, human
  • DNA-Binding Proteins
  • Nuclear Proteins
  • DNA

Supplementary concepts

  • Early-onset ataxia with oculomotor apraxia and hypoalbuminemia

Associated data

  • PDB/3SZQ