4ix7
Crystal Structure of the insv-BEN domain complexed to its DNA target site
Structural highlights
FunctionINSV_DROME Can act as both a transcriptional repressor and corepressor. Represses the expression of genes involved in neural development and preferentially binds palindromic sequence 5'-CCAATTGG-3' to mediate transcriptional repression (PubMed:23468431, PubMed:25561495). Acts as a corepressor for suppressor of hairless (Su(H)) and inhibits Notch signaling during peripheral nervous system development (PubMed:21765394, PubMed:25561495).[1] [2] [3] Publication Abstract from PubMedWe recently reported that Drosophila Insensitive (Insv) promotes sensory organ development and has activity as a nuclear corepressor for the Notch transcription factor Suppressor of Hairless [Su(H)]. Insv lacks domains of known biochemical function but contains a single BEN domain (i.e., a "BEN-solo" protein). Our chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) analysis confirmed binding of Insensitive to Su(H) target genes in the Enhancer of split gene complex [E(spl)-C]; however, de novo motif analysis revealed a novel site strongly enriched in Insv peaks (TCYAATHRGAA). We validate binding of endogenous Insv to genomic regions bearing such sites, whose associated genes are enriched for neural functions and are functionally repressed by Insv. Unexpectedly, we found that the Insv BEN domain binds specifically to this sequence motif and that Insv directly regulates transcription via this motif. We determined the crystal structure of the BEN-DNA target complex, revealing homodimeric binding of the BEN domain and extensive nucleotide contacts via alpha helices and a C-terminal loop. Point mutations in key DNA-contacting residues severely impair DNA binding in vitro and capacity for transcriptional regulation in vivo. We further demonstrate DNA-binding and repression activities by the mammalian neural BEN-solo protein BEND5. Altogether, we define novel DNA-binding activity in a conserved family of transcriptional repressors, opening a molecular window on this extensive gene family. The BEN domain is a novel sequence-specific DNA-binding domain conserved in neural transcriptional repressors.,Dai Q, Ren A, Westholm JO, Serganov AA, Patel DJ, Lai EC Genes Dev. 2013 Mar 6. PMID:23468431[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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