A conserved fertilization complex bridges sperm and egg in vertebrates

IF 5.7 1区化学 Q2 CHEMISTRY, PHYSICAL

Journal of Chemical Theory and Computation Pub Date : 2024-10-17 DOI:10.1016/j.cell.2024.09.035

Victoria E. Deneke, Andreas Blaha, Yonggang Lu, Johannes P. Suwita, Jonne M. Draper, Clara S. Phan, Karin Panser, Alexander Schleiffer, Laurine Jacob, Theresa Humer, Karel Stejskal, Gabriela Krssakova, Elisabeth Roitinger, Dominik Handler, Maki Kamoshita, Tyler D.R. Vance, Xinyin Wang, Joachim M. Surm, Yehu Moran, Jeffrey E. Lee, Andrea Pauli

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Abstract

Fertilization, the basis for sexual reproduction, culminates in the binding and fusion of sperm and egg. Although several proteins are known to be crucial for this process in vertebrates, the molecular mechanisms remain poorly understood. Using an AlphaFold-Multimer screen, we identified the protein Tmem81 as part of a conserved trimeric sperm complex with the essential fertilization factors Izumo1 and Spaca6. We demonstrate that Tmem81 is essential for male fertility in zebrafish and mice. In line with trimer formation, we show that Izumo1, Spaca6, and Tmem81 interact in zebrafish sperm and that the human orthologs interact in vitro. Notably, complex formation creates the binding site for the egg fertilization factor Bouncer in zebrafish. Together, our work presents a comprehensive model for fertilization across vertebrates, where a conserved sperm complex binds to divergent egg proteins—Bouncer in fish and JUNO in mammals—to mediate sperm-egg interaction.

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脊椎动物中连接精子和卵子的保守受精复合体

受精是有性生殖的基础，精子和卵子的结合与融合是受精的高潮。尽管已知脊椎动物中有几种蛋白质对这一过程至关重要，但人们对其分子机制仍然知之甚少。通过 AlphaFold 多聚体筛选，我们鉴定出了蛋白 Tmem81，它与重要的受精因子 Izumo1 和 Spaca6 是保守的三聚体精子复合物的一部分。我们证明了 Tmem81 对斑马鱼和小鼠的雄性生育能力至关重要。与三聚体的形成相一致，我们证明了 Izumo1、Spaca6 和 Tmem81 在斑马鱼精子中的相互作用以及人类直向同源物在体外的相互作用。值得注意的是，复合物的形成为斑马鱼的卵子受精因子 Bouncer 创造了结合位点。我们的工作为脊椎动物的受精过程提供了一个全面的模型，在这个模型中，一个保守的精子复合物与不同的卵蛋白结合--鱼类中的Bouncer和哺乳动物中的JUNO--从而介导精子与卵子的相互作用。

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来源期刊

Journal of Chemical Theory and Computation 化学-物理：原子、分子和化学物理

CiteScore

9.90

自引率

16.40%

发文量

568

审稿时长

1 months

期刊介绍： The Journal of Chemical Theory and Computation invites new and original contributions with the understanding that, if accepted, they will not be published elsewhere. Papers reporting new theories, methodology, and/or important applications in quantum electronic structure, molecular dynamics, and statistical mechanics are appropriate for submission to this Journal. Specific topics include advances in or applications of ab initio quantum mechanics, density functional theory, design and properties of new materials, surface science, Monte Carlo simulations, solvation models, QM/MM calculations, biomolecular structure prediction, and molecular dynamics in the broadest sense including gas-phase dynamics, ab initio dynamics, biomolecular dynamics, and protein folding. The Journal does not consider papers that are straightforward applications of known methods including DFT and molecular dynamics. The Journal favors submissions that include advances in theory or methodology with applications to compelling problems.