For more than 50 years, the methylation of mammalian actin at histidine 73 has been known to occur1. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.SETD3 methylates mammalian actin at His73, and SETD3 deficiency impairs stimulus-induced contraction in primary human uterine smooth muscle cells and leads to maternal dystocia in mice.

中文翻译：

---

SETD3 是一种肌动蛋白组氨酸甲基转移酶，可预防原发性难产

50 多年来，已知会发生哺乳动物肌动蛋白在组氨酸 73 处的甲基化 1。尽管 His73 甲基化普遍存在，我们发现它在几种模式动物和植物中是保守的，但其功能仍不清楚，产生这种修饰的酶也是未知的。在这里，我们将 SET 结构域蛋白 3 (SETD3) 确定为生理肌动蛋白 His73 甲基转移酶。结构研究表明，广泛的相互作用网络将肌动蛋白肽夹在 SETD3 的表面上，以使 His73 在催化口袋内正确定向并促进甲基转移。His73 甲基化降低了肌动蛋白单体的核苷酸交换率，并适度加速了肌动蛋白丝的组装。缺乏SETD3的小鼠在几个组织中显示出肌动蛋白His73甲基化完全丧失，定量蛋白质组学分析表明肌动蛋白His73甲基化是SETD3唯一可检测的生理底物。SETD3 缺陷雌性小鼠的产仔数严重减少，这是由于原发性母体难产对催产素诱导剂无效。此外，SETD3 的消耗会损害原代人子宫平滑肌细胞中信号诱导的收缩。总之，我们的结果确定了哺乳动物组氨酸甲基转移酶，并揭示了 SETD3 和肌动蛋白 His73 甲基化在调节平滑肌收缩性中的关键作用。我们的数据还支持更广泛的假设，即蛋白质组氨酸甲基化作为一种​​常见的调节机制。SETD3 在 His73 甲基化哺乳动物肌动蛋白，