Structural ontogeny of protein-protein interactions

Researchers explored how protein-protein interaction surfaces develop over evolutionary time, motivated partly by the challenge of drugging protein surfaces that lack obvious binding pockets. Using a technique called synthetic coevolution, they engineered novel interactions between protein surfaces that don't naturally bind one another, effectively recreating the early stages of protein complex formation from scratch. This produced seven distinct structural families of complexes involving the protein Z-domain. Compared to naturally evolved binding sites—which converge on a single, geometrically consistent low-energy configuration—these synthetic complexes sampled multiple shallow energy minima through flexible, ratchet-like docking arrangements. By applying machine learning to map the fitness landscape and then performing epistasis analysis, the team identified early "seed" contacts that nucleate the initial encounter between partners. The findings suggest that evolutionarily naive protein surfaces are intrinsically biased against tight binding, possibly because evolution has actively selected against promiscuous interactions at these sites.

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Driving forward the restoration of an American icon

The American chestnut was once a dominant tree in eastern North American forests before being devastated by chestnut blight in the early twentieth century. Efforts to restore it have long relied on traditional crossbreeding with blight-resistant Asian chestnut species, but this approach is slow and risks diluting the tree's native genetic identity. Researchers are now exploring how genomic tools and improved genetic transformation techniques could accelerate and refine this work. By leveraging genome sequencing to better understand resistance mechanisms and developing more efficient methods to introduce targeted genetic modifications, scientists aim to produce trees that are both authentically American chestnut and durably resistant to the fungal pathogen responsible for the blight. These advances could mark a significant turning point in restoration efforts for a species that played a keystone ecological and cultural role before its near-extinction.

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Poxvirus attack of antiviral defense pathways unleashes an effector-triggered NF-κB response

Researchers explored whether mammals use "effector-triggered immunity" (ETI) — a surveillance strategy well-characterized in plants — to detect viral proteins that sabotage host defenses. They built a screening platform in which individual poxvirus virulence factors were expressed in human monocyte cells, with transcriptional responses measured by RNA sequencing. This approach identified a myxoma virus protein, M3.1, that activated the inflammatory transcription factor NF-κB. Further investigation revealed that M3.1 disables two antiviral complexes involving the proteins N4BP1, ZC3H12A, and TBK1 — all of which normally act as brakes on NF-κB signaling. By attacking these negative regulators, M3.1 inadvertently triggers the very immune response it was presumably meant to suppress. The work establishes a scalable method for uncovering ETI pathways in mammals and highlights how proteins that dampen immune signaling can double as sensors that detect pathogen interference.

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Genomic approaches to accelerate American chestnut restoration

Efforts to restore the American chestnut—decimated over a century ago by introduced fungal pathogens—have relied on crossbreeding with disease-resistant Chinese chestnuts, but progress has been hampered by the complexity of resistance genetics. Researchers compared full reference genomes, gene expression patterns, and stem metabolite profiles between the two species to pinpoint the biological basis of blight resistance. They then phenotyped and genotyped large numbers of hybrid trees to identify promising breeding targets. Simulations and direct inoculation trials indicate that meaningful resistance improvements are achievable in trees retaining roughly 70–85% American chestnut ancestry, preserving much of the species' native genetic character. The genomic resources and datasets generated provide a practical foundation for developing diverse, disease-resistant restoration populations that can also compete effectively in natural forest environments.

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