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bioRxiv · 10.1101/2025.08.25.672138

Translation-driven temporal control for intertwined protein assembly

Till, K.·Sunderlikova, V.·Tippmann, F.·Jevtic, P.·Bertolini, M.·Fenzl, K.·Schmitt, J.·Katranidis, A.·Bukau, B.·Kramer, G.·Rape, M.·Tans, S.
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Abstract

Protein complexes are essential to cells. However, how structurally intertwined protein subunits can assemble faithfully is poorly understood. Here, we reveal a "temporal control" mechanism driven by coupled ribosomes to form intertwined dimers. Using Disome Selective Profiling and optical tweezers, we show that the BTB domains of KEAP1, KLHL12, and PATZ1 form stable closed states as monomers, thus impeding proposed domain-swapping assembly routes. By contrast, the timed emergence of nascent chain segments during translation enables alternative folding-assembly pathways that bypass the closed monomeric state. Analysis indicates that this mechanism works in concert with dimerization quality control by the E3 ligase SCF-FBXL17, and is relevant across the BTB domain family. This study shows that ribosome cooperation expands the range of possible protein architectures.

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Till, K., Sunderlikova, V., Tippmann, F., Jevtic, P., Bertolini, M., Fenzl, K., Schmitt, J., Katranidis, A., Bukau, B., Kramer, G., Rape, M., Tans, S.. 2025-08-29. Translation-driven temporal control for intertwined protein assembly. https://doi.org/10.1101/2025.08.25.672138

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