5z2t

Crystal structure of DNA-bound DUX4-HD2

spinqualitylabelsall models 5z2t, resolution 2.62Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5z2t is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.623Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease DUX4_HUMAN Facioscapulohumeral dystrophy. The gene represented in this entry is involved in disease pathogenesis. The disease is caused by deletion of an integral number of units of a 3.3-kb tandem repeats, termed D4Z4 macrosatellite, located on chromosome 4q35. In unaffected subjects, the D4Z4 array consists of 11-150 repeats, while in FSHD1 patients, the array is reduced to 1-10 repeats (PubMed:19320656). DUX4 is located in D4Z4 macrosatellite which is epigenetically repressed in somatic tissues. D4Z4 chromatin relaxation in FSHD1 results in inefficient epigenetic repression of DUX4 and a variegated pattern of DUX4 protein expression in a subset of skeletal muscle nuclei. Ectopic expression of DUX4 in skeletal muscle activates the expression of stem cell and germline genes, and, when overexpressed in somatic cells, DUX4 can ultimately lead to cell death. Function DUX4_HUMAN Involved in transcriptional regulation. May regulate microRNA (miRNA) expression. Publication Abstract from PubMed Oncogenic fusions are major drivers in leukemogenesis and may serve as potent targets for treatment. DUX4/IGHs have been shown to trigger the abnormal expression of ERGalt through binding to DUX4-Responsive-Element (DRE), which leads to B-cell differentiation arrest and a full-fledged B-ALL. Here, we determined the crystal structures of Apo- and DNADRE-bound DUX4HD2 and revealed a clamp-like transactivation mechanism via the double homeobox domain. Biophysical characterization showed that mutations in the interacting interfaces significantly impaired the DNA binding affinity of DUX4 homeobox. These mutations, when introduced into DUX4/IGH, abrogated its transactivation activity in Reh cells. More importantly, the structure-based mutants significantly impaired the inhibitory effects of DUX4/IGH upon B-cell differentiation in mouse progenitor cells. All these results help to define a key DUX4/IGH-DRE recognition/step in B-ALL. Structural basis of DUX4/IGH-driven transactivation.,Dong X, Zhang W, Wu H, Huang J, Zhang M, Wang P, Zhang H, Chen Z, Chen SJ, Meng G Leukemia. 2018 Mar 15. pii: 10.1038/s41375-018-0093-1. doi:, 10.1038/s41375-018-0093-1. PMID:29572508 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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