人源 DPPA3 与 UHRF1 PHD 指结合的结构揭示了其与鼠源 DPPA3 的功能和结构差异。
Structure of human DPPA3 bound to the UHRF1 PHD finger reveals its functional and structural differences from mouse DPPA3.
机构信息
Structural Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
Structural Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
出版信息
Commun Biol. 2024 Jun 19;7(1):746. doi: 10.1038/s42003-024-06434-9.
DNA methylation maintenance is essential for cell fate inheritance. In differentiated cells, this involves orchestrated actions of DNMT1 and UHRF1. In mice, the high-affinity binding of DPPA3 to the UHRF1 PHD finger regulates UHRF1 chromatin dissociation and cytosolic localization, which is required for oocyte maturation and early embryo development. However, the human DPPA3 ortholog functions during these stages remain unclear. Here, we report the structural basis for human DPPA3 binding to the UHRF1 PHD finger. The conserved human DPPA3 VRT motif binds to the acidic surface of UHRF1 PHD finger, whereas mouse DPPA3 binding additionally utilizes two unique α-helices. The binding affinity of human DPPA3 for the UHRF1 PHD finger was weaker than that of mouse DPPA3. Consequently, human DPPA3, unlike mouse DPPA3, failed to inhibit UHRF1 chromatin binding and DNA remethylation in Xenopus egg extracts effectively. Our data provide novel insights into the distinct function and structure of human DPPA3.
DNA 甲基化维持对于细胞命运的遗传至关重要。在分化细胞中，这涉及 DNMT1 和 UHRF1 的协调作用。在小鼠中，DPPA3 与 UHRF1 PHD 手指的高亲和力结合调节 UHRF1 染色质解离和细胞质定位，这对于卵母细胞成熟和早期胚胎发育是必需的。然而，人类 DPPA3 同源物在这些阶段的功能仍不清楚。在这里，我们报告了人类 DPPA3 与 UHRF1 PHD 手指结合的结构基础。保守的人类 DPPA3 VRT 基序结合到 UHRF1 PHD 手指的酸性表面，而小鼠 DPPA3 结合另外利用两个独特的 α-螺旋。人类 DPPA3 与 UHRF1 PHD 手指的结合亲和力弱于小鼠 DPPA3。因此，与小鼠 DPPA3 不同，人类 DPPA3 未能有效地抑制 Xenopus 卵提取物中 UHRF1 染色质结合和 DNA 再甲基化。我们的数据为人类 DPPA3 的独特功能和结构提供了新的见解。
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