Human ubiquitin ligase HERC2, a component of the DNA repair machinery, has been linked to neurological diseases and cancer. Here, we show that the ZZ domain of HERC2 (HERC2_ZZ) binds to histone H3 tail and tolerates posttranslational modifications commonly present in H3. The crystal structure of the HERC2_ZZ:H3 complex provides the molecular basis for this interaction and highlights a critical role of the negatively charged site of HERC2_ZZ in capturing of A1 of H3. NMR, mutagenesis, and fluorescence data reveal that HERC2_ZZ binds to H3 and the N-terminal tail of SUMO1, a previously reported ligand of HERC2_ZZ, with comparable affinities. Like H3, the N-terminal tail of SUMO1 occupies the same negatively charged site of HERC2_ZZ in the crystal structure of the complex, although in contrast to H3 it adopts an α-helical conformation. Our data suggest that HERC2_ZZ may play a role in mediating the association of HERC2 with chromatin.

人类泛素连接酶 HERC2 是 DNA 修复机制的一个组成部分，与神经系统疾病和癌症有关。在这里，我们展示了 HERC2 的 ZZ 结构域 (HERC2 _ZZ ) 与组蛋白 H3 尾部结合并耐受 H3 中常见的翻译后修饰。HERC2 _ZZ :H3 复合物的晶体结构为这种相互作用提供了分子基础，并突出了 HERC2 _ZZ带负电荷位点在捕获 H3 的 A1 中的关键作用。核磁共振、诱变和荧光数据显示 HERC2 _ZZ与 H3 和SUMO1的 N 末端尾部结合，SUMO1 是先前报道的 HERC2 _ZZ配体，具有可比的亲和力。与 H3 一样，SUMO1 的 N 末端尾部在复合物的晶体结构中占据与 HERC2 _ZZ相同的带负电荷的位点，尽管与 H3 相比，它采用α-螺旋构象。我们的数据表明 HERC2 _ZZ可能在介导 HERC2 与染色质的关联中发挥作用。