Grimm Clemens, Matos Raquel, Ly-Hartig Nga, Steuerwald Ulrich, Lindner Doris, Rybin Vladimir, Müller Jürg, Müller Christoph W
European Molecular Biology Laboratory, Grenoble Outstation, Grenoble, France.
EMBO J. 2009 Jul 8;28(13):1965-77. doi: 10.1038/emboj.2009.147. Epub 2009 Jun 4.
Polycomb group (PcG) proteins repress transcription by modifying chromatin structure in target genes. dSfmbt is a subunit of the Drosophila melanogaster PcG protein complex PhoRC and contains four malignant brain tumour (MBT) repeats involved in the recognition of various mono- and dimethylated histone peptides. Here, we present the crystal structure of the four-MBT-repeat domain of dSfmbt in complex with a mono-methylated histone H4 peptide. Only a single histone peptide binds to the four-MBT-repeat domain. Mutational analyses show high-affinity binding with low peptide sequence selectivity through combinatorial interaction of the methyl-lysine with an aromatic cage and positively charged flanking residues with the surrounding negatively charged surface of the fourth MBT repeat. dSfmbt directly interacts with the PcG protein Scm, a related MBT-repeat protein with similar methyl-lysine binding activity. dSfmbt and Scm co-occupy Polycomb response elements of target genes in Drosophila and they strongly synergize in the repression of these target genes, suggesting that the combined action of these two MBT proteins is crucial for Polycomb silencing.
多梳蛋白组(PcG)蛋白通过修饰靶基因的染色质结构来抑制转录。dSfmbt是果蝇PcG蛋白复合物PhoRC的一个亚基,包含四个恶性脑肿瘤(MBT)重复序列,参与识别各种单甲基化和二甲基化组蛋白肽段。在此,我们展示了与单甲基化组蛋白H4肽段结合的dSfmbt的四MBT重复结构域的晶体结构。只有一个组蛋白肽段与四MBT重复结构域结合。突变分析表明,通过甲基化赖氨酸与芳香笼的组合相互作用以及带正电荷的侧翼残基与第四个MBT重复序列周围带负电荷表面的相互作用,该结构域与肽段具有高亲和力结合且肽段序列选择性低。dSfmbt直接与PcG蛋白Scm相互作用,Scm是一种具有相似甲基化赖氨酸结合活性的相关MBT重复蛋白。在果蝇中,dSfmbt和Scm共同占据靶基因的多梳反应元件,并且它们在抑制这些靶基因方面具有强烈的协同作用,这表明这两种MBT蛋白的联合作用对于多梳沉默至关重要。