Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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).

Original publication

DOI

10.1038/nsmb.2146

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

09/10/2011

Volume

18

Pages

1189 - 1195

Keywords

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