Functional significance of mutations in the Snf2 domain of ATRX

被引:40
|
作者
Mitson, Matthew [1 ]
Kelley, Lawrence A. [2 ]
Sternberg, Michael J. E. [2 ]
Higgs, Douglas R. [1 ]
Gibbons, Richard J. [1 ]
机构
[1] John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Oxford OX3 9DS, England
[2] Univ London Imperial Coll Sci Technol & Med, Dept Life Sci, Div Mol Biosci, Struct Bioinformat Grp, London SW7 2AZ, England
关键词
X SYNDROME PROTEIN; DNA TRANSLOCATION; STRUCTURE PREDICTION; REMODELING ENZYME; HISTONE CHAPERONE; CHROMATIN; COMPLEX; DAXX; H3.3; ISWI;
D O I
10.1093/hmg/ddr163
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2603 / 2610
页数:8
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