Structures and chemical shift assignments for the ADD domain of the ATRX protein
[ATRX_HUMAN] Defects in ATRX are the cause of alpha-thalassemia mental retardation syndrome X-linked (ATRX) [MIM:301040]. ATR-X is an X-linked disorder comprising severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions.          Defects in ATRX are the cause of mental retardation syndromic X-linked with hypotonic facies syndrome type 1 (MRXSHF1) [MIM:309580]; also called Carpenter-Waziri syndrome (CWS), Juberg-Marsidi syndrome (JMS), Smith-Fineman-Myers syndrome type 1 (SFM1). Clinical features include severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.      Defects in ATRX are a cause of alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:300448]. In this disorder, alpha-thalassemia occurs as an acquired abnormality in association with a multilineage myelodysplasia.
[ATRX_HUMAN] Could be a global transcriptional regulator. Modifies gene expression by affecting chromatin. May be involved in brain development and facial morphogenesis.
Publication Abstract from PubMed
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.
Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX.,Argentaro A, Yang JC, Chapman L, Kowalczyk MS, Gibbons RJ, Higgs DR, Neuhaus D, Rhodes D Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11939-44. Epub 2007 Jul 3. PMID:17609377
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.