Structural duality enables a single protein to act as a toxin-antidote pair for meiotic drive

Area of Science:

• Genetics
• Molecular Biology
• Cell Biology

Background:

• Selfish genetic elements called killer meiotic drivers (KMDs) manipulate inheritance by eliminating gametes lacking them.
• Most KMDs operate via a toxin-antidote mechanism, where a toxin kills all gametes, and an antidote confers resistance only to carriers.
• The fission yeast *Schizosaccharomyces pombe* harbors the KMD element *tdk1*, whose mechanism remained largely uncharacterized.

Purpose of the Study:

• To investigate the molecular mechanism by which the *tdk1* element biases inheritance in *Schizosaccharomyces pombe*.
• To determine if a single protein product is responsible for both the toxic and antidote functions of *tdk1*.
• To elucidate the structural and functional transitions of the Tdk1 protein.

Main Methods:

• Biochemical assays to analyze Tdk1 protein structure and function in different cellular contexts (vegetative growth, meiosis, spores, germination).
• Interaction studies to identify proteins interacting with the toxic form of Tdk1, including histone reader Bdf1.
• Genetic manipulation of *tdk1* to create "toxin-only" and "antidote-only" constructs for functional reconstitution experiments.

Main Results:

• The *tdk1* KMD utilizes a single protein, Tdk1, for both killing and resistance.
• Tdk1 exists as a nontoxic tetramer during vegetative growth and meiosis but forms a toxic, spore-specific form.
• The toxic Tdk1 interacts with Bdf1, forms supramolecular foci, and disrupts mitosis in non-carrier spores after germination.
• Tdk1 synthesized during carrier spore germination acts as an antidote, dismantling toxic Tdk1 assemblies.
• Structural analysis revealed the N-terminal region's role in autoinhibition and assembly of toxic foci.
• A functional KMD was reconstituted using separate "toxin-only" and "antidote-only" Tdk1 expression constructs.

Conclusions:

• *tdk1* employs a single protein with structural duality to achieve a toxin-antidote system, a novel mechanism for KMDs.
• Tdk1's ability to switch between autoinhibited and active forms underlies its dual role in inheritance bias.
• This study expands the understanding of toxin-antidote systems and selfish genetic element evolution.