CHIP (C-terminus of Hsc70-interacting protein) and its worm ortholog CHN-1 are E3 ubiquitin ligases that link the chaperone system with the ubiquitin-proteasome system (UPS). CHN-1 can cooperate with UFD-2, another E3 ligase, to accelerate ubiquitin chain formation; however, the basis for the high processivity of this E3s set has remained obscure. Here, we studied the molecular mechanism and function of the CHN-1–UFD-2 complex in Caenorhabditis elegans. Our data show that UFD-2 binding promotes the cooperation between CHN-1 and ubiquitin-conjugating E2 enzymes by stabilizing the CHN-1 U-box dimer. However, HSP70/HSP-1 chaperone outcompetes UFD-2 for CHN-1 binding, thereby promoting a shift to the autoinhibited CHN-1 state by acting on a conserved residue in its U-box domain. The interaction with UFD-2 enables CHN-1 to efficiently ubiquitylate and regulate S-adenosylhomocysteinase (AHCY-1), a key enzyme in the S-adenosylmethionine (SAM) regeneration cycle, which is essential for SAM-dependent methylation. Our results define the molecular mechanism underlying the synergistic cooperation of CHN-1 and UFD-2 in substrate ubiquitylation.

中文翻译：

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异型组装机制调节 CHIP E3 连接酶活性

CHIP（Hsc70 相互作用蛋白的 C 末端）及其蠕虫直向同源物 CHN-1 是 E3 泛素连接酶，可将伴侣系统与泛素-蛋白酶体系统 (UPS) 连接起来。CHN-1可与另一种E3连接酶UFD-2配合，加速泛素链的形成；然而，这套 E3 的高持续性的基础仍然模糊不清。在这里，我们研究了秀丽隐杆线虫中 CHN-1-UFD-2 复合物的分子机制和功能. 我们的数据表明，UFD-2 结合通过稳定 CHN-1 U-box 二聚体促进了 CHN-1 和泛素结合 E2 酶之间的合作。然而，HSP70/HSP-1 伴侣在 CHN-1 结合方面的竞争胜过 UFD-2，从而通过作用于其 U-box 结构域中的保守残基促进向自身抑制 CHN-1 状态的转变。与 UFD-2 的相互作用使 CHN-1 能够有效地泛素化和调节S-腺苷高半胱氨酸酶 (AHCY-1)，它是S-腺苷甲硫氨酸 (SAM) 再生循环中的关键酶，对 SAM 依赖性甲基化至关重要。我们的结果定义了 CHN-1 和 UFD-2 在底物泛素化中协同合作的分子机制。