A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes
A bidentate Polycomb Repressive-Deubiquitinase complex is required for efficient activity on nucleosomes
复制标题
DOI：
10.1038/s41467-018-06186-1
复制
发表时间：
2018-09-26
影响因子：
16.6
通讯作者：
Mace, Peter D.
中科院分区：
文献类型：
--
作者：
Foglizzo, Martina;Middleton, Adam J.;Mace, Peter D.
泛素与组蛋白 2A (H2AK119Ub) 赖氨酸 119 的连接是受抑制发育基因的表观遗传标记特征，可被 Polycomb 抑制去泛素酶 (PR-DUB) 复合物去除。在这里，我们报告了果蝇 PR-DUB 的晶体结构，揭示了去泛素酶 Calypso 及其激活伙伴 ASX 形成了 2:2 复合物。双齿 Calypso-ASX 复合物是通过两个激活的 Calypso 蛋白通过其卷曲螺旋区域二聚化而生成的。破坏 Calypso 二聚体界面不会影响固有的催化活性，但会因核小体募集受损而抑制 H2AK119Ub 的去除。人类对应物 BAP1 的等效表面发生突变也会损害核小体的活性。总之，这表明高局部浓度驱动双齿 PR-DUB 复合物在染色质上的组装，为增强特定基因组灶点的 PR-DUB 活性以及不同类别的 PR-DUB 突变对肿瘤发生的影响提供了机制基础。
Attachment of ubiquitin to lysine 119 of Histone 2A (H2AK119Ub) is an epigenetic mark characteristic of repressed developmental genes, which is removed by the Polycomb Repressive-Deubiquitinase (PR-DUB) complex. Here we report the crystal structure of the Drosophila PR-DUB, revealing that the deubiquitinase Calypso and its activating partner ASX form a 2:2 complex. The bidentate Calypso-ASX complex is generated by dimerisation of two activated Calypso proteins through their coiled-coil regions. Disrupting the Calypso dimer interface does not affect inherent catalytic activity, but inhibits removal of H2AK119Ub as a consequence of impaired recruitment to nucleosomes. Mutating the equivalent surface on the human counterpart, BAP1, also compromises activity on nucleosomes. Together, this suggests that high local concentrations drive assembly of bidentate PR-DUB complexes on chromatin-providing a mechanistic basis for enhanced PR-DUB activity at specific genomic foci, and the impact of distinct classes of PR-DUB mutations in tumorigenesis.