National Institute of Biological Sciences, Beijing 102206, China.
Key Laboratory of RNA Science and Engineering, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Proc Natl Acad Sci U S A. 2024 Nov 5;121(45):e2408618121. doi: 10.1073/pnas.2408618121. Epub 2024 Nov 1.
In sexual reproduction, selfish genetic elements known as killer meiotic drivers (KMDs) bias inheritance by eliminating gametes that do not carry them. The selective killing behavior of most KMDs can be explained by a toxin-antidote model, where a toxin harms all gametes while an antidote provides resistance to the toxin in carriers. This study investigates whether and how the KMD element in the fission yeast deploys this strategy. Intriguingly, relies on a single protein product, Tdk1, for both killing and resistance. We show that Tdk1 exists in a nontoxic tetrameric form during vegetative growth and meiosis but transforms into a distinct toxic form in spores. This toxic form acquires the ability to interact with the histone reader Bdf1 and assembles into supramolecular foci that disrupt mitosis in noncarriers after spore germination. In contrast, Tdk1 synthesized during germination of carrier spores is nontoxic and acts as an antidote, dismantling the preformed toxic Tdk1 assemblies. Replacement of the N-terminal region of Tdk1 with a tetramer-forming peptide reveals its dual roles in imposing an autoinhibited tetrameric conformation and facilitating the assembly of supramolecular foci when autoinhibition is released. Moreover, we successfully reconstituted a functional KMD element by combining a construct that exclusively expresses Tdk1 during meiosis ("toxin-only") with another construct that expresses Tdk1 specifically during germination ("antidote-only"). This work uncovers a remarkable example of a single protein employing structural duality to form a toxin-antidote pair, expanding our understanding of the mechanisms underlying toxin-antidote systems.
在有性生殖中，自私的遗传因子，即 killer 减数分裂驱动因子（KMD），通过消除不携带它们的配子来偏向遗传。大多数 KMD 的选择杀伤行为可以用毒素-解毒剂模型来解释，其中毒素会伤害所有的配子，而解毒剂则为携带者提供对毒素的抗性。本研究调查了裂殖酵母中的 KMD 元素是否以及如何部署这种策略。有趣的是，它依赖于一种单一的蛋白质产物 Tdk1，既能发挥杀伤作用，又能提供抗性。我们发现，Tdk1 在营养生长和减数分裂期间以非毒性四聚体形式存在，但在孢子中转化为独特的毒性形式。这种毒性形式获得了与组蛋白阅读器 Bdf1 相互作用的能力，并组装成超分子焦点，在孢子萌发后破坏非携带者的有丝分裂。相比之下，在携带者孢子萌发期间合成的 Tdk1 是非毒性的，并作为解毒剂发挥作用，破坏预先形成的毒性 Tdk1 组装体。用四聚体形成肽替换 Tdk1 的 N 端区域揭示了其在施加自动抑制的四聚体构象和促进超分子焦点组装方面的双重作用，当自动抑制被释放时。此外，我们通过将仅在减数分裂期间表达 Tdk1 的构建体（“仅毒素”）与另一个仅在萌发期间表达 Tdk1 的构建体（“仅解毒剂”）结合，成功地重建了一个功能性 KMD 元素。这项工作揭示了一种单一蛋白质利用结构双重性形成毒素-解毒剂对的显著例子，扩展了我们对毒素-解毒剂系统背后机制的理解。
