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PDBsum entry 2ld1
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Metal binding protein
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PDB id
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2ld1
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References listed in PDB file
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Key reference
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Title
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Structural consequences of disease-Causing mutations in the atrx-Dnmt3-Dnmt3l (add) domain of the chromatin-Associated protein atrx.
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Authors
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A.Argentaro,
J.C.Yang,
L.Chapman,
M.S.Kowalczyk,
R.J.Gibbons,
D.R.Higgs,
D.Neuhaus,
D.Rhodes.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
11939-11944.
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PubMed id
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Abstract
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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.
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