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Crystal structure of human DUX4 homeodomains bound to A11G DNA mutantCrystal structure of human DUX4 homeodomains bound to A11G DNA mutant
Structural highlights
DiseaseDUX4_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.[1] FunctionDUX4_HUMAN Involved in transcriptional regulation. May regulate microRNA (miRNA) expression.[2] [3] Publication Abstract from PubMedDUX4 plays critical role in the molecular pathogenesis of the neuromuscular disorder facioscapulohumeral muscular dystrophy and acute lymphoblastic leukemia in humans. As a master transcription regulator, DUX4 can also bind the promoters and activate the transcription of hundreds ZGA-associated genes. Here we report on the structural and biochemical studies of DUX4 double homeodomains (DUX4-DH), representing the only structures contain both homeodomain 1 (HD1) and homeodomain 2 (HD2). HD1 and HD2 adopt classical homeobox fold; via the helix inserted into the major groove and the N-terminal extended loop inserted into the minor groove, HD1 and HD2 recognize the box1 (5'-TAA-3') and box2 (5'-TGA-3') nucleotides of the consensus sequence, respectively. Among the box1 and box2 linking nucleotides (CCTAA), the two adenine residues are reported to be highly conserved; however, they are not directly recognized by DUX4-DH in the structures. Besides different nucleotides, our ITC analysis indicated that DUX4-DH can also tolerate various changes in the linker length. Our studies not only revealed the basis for target DNA recognition by DUX4, but also advanced our understanding on multiple gene activation by DUX4. Structural basis for multiple gene regulation by human DUX4.,Li Y, Wu B, Liu H, Gao Y, Yang C, Chen X, Zhang J, Chen Y, Gu Y, Li J, Ma J, Gan J Biochem Biophys Res Commun. 2018 Oct 12. pii: S0006-291X(18)32202-2. doi:, 10.1016/j.bbrc.2018.10.056. PMID:30322619[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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