Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA; Howard Hughes Medical Institute, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cell Rep. 2018 Jun 26;23(13):3769-3775. doi: 10.1016/j.celrep.2018.05.095.
FOG-3 is a master regulator of sperm fate in Caenorhabditis elegans and homologous to Tob/BTG proteins, which in mammals are monomeric adaptors that recruit enzymes to RNA binding proteins. Here, we determine the FOG-3 crystal structure and in vitro demonstrate that FOG-3 forms dimers that can multimerize. The FOG-3 multimeric structure has a basic surface potential, suggestive of binding nucleic acid. Consistent with that prediction, FOG-3 binds directly to nearly 1,000 RNAs in nematode spermatogenic germ cells. Most binding is to the 3' UTR, and most targets (94%) are oogenic mRNAs, even though assayed in spermatogenic cells. When tethered to a reporter mRNA, FOG-3 represses its expression. Together these findings elucidate the molecular mechanism of sperm fate specification and reveal the evolution of a protein from monomeric to multimeric form with acquisition of a distinct mode of mRNA repression.
FOG-3 是秀丽隐杆线虫精子命运的主要调节因子，与 Tob/BTG 蛋白同源，Tob/BTG 蛋白在哺乳动物中是单体衔接子，可将酶募集到 RNA 结合蛋白上。在这里，我们确定了 FOG-3 的晶体结构，并在体外证明 FOG-3 形成二聚体，二聚体可以多聚化。FOG-3 的多聚体结构具有基本的表面电势，表明可以结合核酸。与该预测一致，FOG-3 直接结合线虫生殖细胞中的近 1000 种 RNA。大多数结合发生在 3'UTR 上，大多数靶标（94%）是卵母细胞 mRNA，尽管在精原细胞中进行了检测。当与报告 mRNA 连接时，FOG-3 会抑制其表达。这些发现共同阐明了精子命运特化的分子机制，并揭示了一种从单体形式进化为多聚体形式的蛋白质，获得了一种独特的 mRNA 抑制模式。
