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The chromatin-associated protein ATRX was originally identified because mutations in the ATRX gene cause a severe form of syndromal X-linked mental retardation associated with alpha-thalassemia. Half of all of the disease-associated missense mutations cluster in a cysteine-rich region in the N terminus of ATRX. This region was named the ATRX-DNMT3-DNMT3L (ADD) domain, based on sequence homology with a family of DNA methyltransferases. Here, we report the solution structure of the ADD domain of ATRX, which consists of an N-terminal GATA-like zinc finger, a plant homeodomain finger, and a long C-terminal alpha-helix that pack together to form a single globular domain. Interestingly, the alpha-helix of the GATA-like finger is exposed and highly basic, suggesting a DNA-binding function for ATRX. The disease-causing mutations fall into two groups: the majority affect buried residues and hence affect the structural integrity of the ADD domain; another group affects a cluster of surface residues, and these are likely to perturb a potential protein interaction site. The effects of individual point mutations on the folding state and stability of the ADD domain correlate well with the levels of mutant ATRX protein in patients, providing insights into the molecular pathophysiology of ATR-X syndrome.

Original publication

DOI

10.1073/pnas.0704057104

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

17/07/2007

Volume

104

Pages

11939 - 11944

Keywords

Amino Acid Sequence, Amino Acid Substitution, Cell Transformation, Viral, Chromatin, DNA Helicases, Herpesvirus 4, Human, Humans, Lymphocytes, Models, Molecular, Molecular Sequence Data, Nuclear Magnetic Resonance, Biomolecular, Nuclear Proteins, Point Mutation, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Alignment, Static Electricity, Structure-Activity Relationship, Surface Properties