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ATRX is a member of the Snf2 family of chromatin-remodelling proteins and is mutated in an X-linked mental retardation syndrome associated with alpha-thalassaemia (ATR-X syndrome). We have carried out an analysis of 21 disease-causing mutations within the Snf2 domain of ATRX by quantifying the expression of the ATRX protein and placing all missense mutations in their structural context by homology modelling. While demonstrating the importance of protein dosage to the development of ATR-X syndrome, we also identified three mutations which primarily affect function rather than protein structure. We show that all three of these mutant proteins are defective in translocating along DNA while one mutant, uniquely for a human disease-causing mutation, partially uncouples adenosine triphosphate (ATP) hydrolysis from DNA binding. Our results highlight important mechanistic aspects in the development of ATR-X syndrome and identify crucial functional residues within the Snf2 domain of ATRX. These findings are important for furthering our understanding of how ATP hydrolysis is harnessed as useful work in chromatin remodelling proteins and the wider family of nucleic acid translocating motors.

Original publication

DOI

10.1093/hmg/ddr163

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/07/2011

Volume

20

Pages

2603 - 2610

Keywords

Amino Acid Sequence, Animals, Cell Line, DNA Helicases, Enzyme Activation, Humans, Insects, Mental Retardation, X-Linked, Models, Molecular, Molecular Sequence Data, Mutation, Nuclear Proteins, Protein Conformation, Protein Stability, Sequence Alignment, Translocation, Genetic, Ubiquitin-Protein Ligases, alpha-Thalassemia