title: Functional significance of mutations in the Snf2 domain of ATRX.
abstract: 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.
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mitson
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Kelley
authors.forename: Michael J E
authors.initials: MJ
authors.lastname: Sternberg
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Higgs
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gibbons
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004265:DNA Helicases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D007313:Insecta; D038901:X-Linked Intellectual Disability / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D055550:Protein Stability; D016415:Sequence Alignment; D014178:Translocation, Genetic / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics*; D000075924:X-linked Nuclear Protein; D017085:alpha-Thalassemia / Q000201:enzymology / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; C516226:SHPRH protein, human; D044767:Ubiquitin-Protein Ligases; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein