ArticleThe Journal of biological chemistry2005
Disease-associated mutations inactivate AMP-lysine hydrolase activity of Aprataxin.
Article in The Journal of biological chemistry, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 60 citations in OpenAlex.
- Ataxia with Ocular Apraxia Type 1 (AOA1) (APTX, W279* Mutation): Neurological, Neuropsychological, and Molecular Outlining of a Heterogenous Phenotype in Four Colombian Siblings.Molecular neurobiology · 2022Article
- Topoisomerase-Mediated DNA Damage in Neurological Disorders.Frontiers in aging neuroscience · 2021Review
- Natural Products Containing 'Rare' Organophosphorus Functional Groups.Molecules (Basel, Switzerland) · 2019Review
- Mechanism of APTX nicked DNA sensing and pleiotropic inactivation in neurodegenerative disease.The EMBO journal · 2018Article
- Clinical, Biomarker, and Molecular Delineations and Genotype-Phenotype Correlations of Ataxia With Oculomotor Apraxia Type 1.JAMA neurology · 2018Article
- Caught with One's Zinc Fingers in the Genome Integrity Cookie Jar.Trends in genetics : TIG · 2018Review
- Identification of a novel mutation in theCold Spring Harbor molecular case studies · 2017Article
- Genome integrity and disease prevention in the nervous system.Genes & development · 2017Review
- Neurological disorders associated with DNA strand-break processing enzymes.Mechanisms of ageing and development · 2017Review
- DNA3'pp5'G de-capping activity of aprataxin: effect of cap nucleoside analogs and structural basis for guanosine recognition.Nucleic acids research · 2015Article
- Identification of activating enzymes of a novel FBPase inhibitor prodrug, CS-917.Pharmacology research & perspectives · 2015Article
- Molecular underpinnings of Aprataxin RNA/DNA deadenylase function and dysfunction in neurological disease.Progress in biophysics and molecular biology · 2015Review
- On the effect of protein conformation diversity in discriminating among neutral and disease related single amino acid substitutions.BMC genomics · 2012Article
- Repair of persistent strand breaks in the mitochondrial genome.Mechanisms of ageing and development · 2012Review
- DNA repair deficiency in neurodegeneration.Progress in neurobiology · 2011Review
- Variation in base excision repair capacity.Mutation research · 2011Review
- Clinical and molecular characterization of ataxia with oculomotor apraxia patients in Saudi Arabia.BMC medical genetics · 2011Article
- To live or to die: a matter of processing damaged DNA termini in neurons.EMBO molecular medicine · 2011Review
- Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin.DNA repair · 2009Article
- Defective DNA ligation during short-patch single-strand break repair in ataxia oculomotor apraxia 1.Molecular and cellular biology · 2009Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Ataxia-oculomotor apraxia syndrome 1 is an early onset cerebellar ataxia that results from loss of function mutations in the APTX gene, encoding Aprataxin, which contains three conserved domains. The forkhead-associated domain of Aprataxin mediates protein-protein interactions with molecules that respond to DNA damage, but the cellular phenotype of the disease does not appear to be consistent with a major loss in DNA damage responses. Disease-associated mutations in Aprataxin target a histidine triad domain that is similar to Hint, a universally conserved AMP-lysine hydrolase, or truncate the protein NH2-terminal to a zinc finger. With novel fluorigenic substrates, we demonstrate that Aprataxin possesses an active-site-dependent AMP-lysine and GMP-lysine hydrolase activity that depends additionally on the zinc finger for protein stability and on the forkhead associated domain for enzymatic activity. Alleles carrying any of eight recessive mutations associated with ataxia and oculomotor apraxia encode proteins with huge losses in protein stability and enzymatic activity, consistent with a null phenotype. The mild presentation allele, APTX-K197Q, associated with ataxia but not oculomotor apraxia, encodes a protein with a mild defect in stability and activity, while enzyme encoded by the atypical presentation allele, APTX-R199H, retained substantial function, consistent with altered and not loss of activity. The data suggest that the essential function of Aprataxin is reversal of nucleotidylylated protein modifications, that all three domains contribute to formation of a stable enzyme, and that the in vitro behavior of cloned APTX alleles can score disease-associated mutations.
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