️ Episode 208: ZAK, Collided Ribosomes, and the Stress Switch

In this episode of PaperCast Base by Base, we explore how collided ribosomes activate the MAP3K ZAK to drive the ribotoxic stress response and shape cell fate decisions under translational stress.

Study Highlights:
Using biochemistry, cryo-electron microscopy and crosslinking-based RNA mapping, the authors define how ZAK is constitutively recruited to ribosomes and how this engagement changes upon stress-induced ribosome collisions. They show that ZAK contacts the 40S subunit through a C-terminal eS27 pin and rRNA patches and anchors to RACK1 via a RACK1-interacting helix, while a collision-sensitive FPxL-containing RACK1-interacting motif becomes engaged only when two ribosomes collide. Disome formation brings two RACK1 molecules into proximity, allowing ZAK SAM domains to dimerize across the collision interface and enabling kinase activation, with pathogenic and engineered SAM variants revealing how this interface tunes activity on and off the ribosome. The study also identifies the ribosome-binding protein SERBP1 as a negative regulator that competes with ZAK for the FPxL-binding site on RACK1, thereby preventing inappropriate activation during basal translation.

Conclusion:
This work provides a structural and mechanistic blueprint for how ribosome collisions are translated into ZAK kinase activation, offering new entry points to modulate stress signalling in disease contexts.

Music:
Enjoy the music based on this article at the end of the episode.

Reference:
Huso VL, Niu S, Catipovic MA, Saba JA, Denk T, Park E, Cheng J, Berninghausen O, Becker T, Green R, Beckmann R. ZAK activation at the collided ribosome. Nature. 2025. https://doi.org/10.1038/s41586-025-09772-8

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode Slug: zak-collided-ribosome-stress-switch

On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.

Chapters

• (00:00:00 ) - The cell's ribotoxic stress response
• (00:05:10 ) - The Rack 1 Collapse Sensor
• (00:09:55 ) - How does the ZK SAM domains dimerize to trigger cell
• (00:12:16 ) - When We Collide