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Co-translational ribosome pairing enables native assembly of misfolding-prone subunits

Author

Listed:
  • Florian Wruck

    (AMOLF)

  • Jaro Schmitt

    (DKFZ-ZMBH Alliance)

  • Katharina Till

    (AMOLF)

  • Kai Fenzl

    (DKFZ-ZMBH Alliance
    European Molecular Biology Laboratory)

  • Matilde Bertolini

    (DKFZ-ZMBH Alliance
    Addition Therapeutics)

  • Frank Tippmann

    (DKFZ-ZMBH Alliance)

  • Alexandros Katranidis

    (Forschungszentrum Jülich (FZJ))

  • Bernd Bukau

    (DKFZ-ZMBH Alliance)

  • Günter Kramer

    (DKFZ-ZMBH Alliance)

  • Sander J. Tans

    (AMOLF
    Bionanoscience Department of Delft University of Technology and Kavli Institute of Nanoscience Delft)

Abstract

Protein complexes are pivotal to most cellular processes. Emerging evidence indicating dimer assembly by pairs of ribosomes suggests yet unknown folding mechanisms involving two nascent chains. Here, we show that co-translational ribosome pairing allows their nascent chains to ‘chaperone each other’, thus enabling the formation of coiled-coil homodimers from subunits that misfold individually. We developed an integrated single-molecule fluorescence and force spectroscopy approach to probe the folding and assembly of two nascent chains extending from nearby ribosomes, using the intermediate filament lamin as a model system. Ribosome proximity during early translation stages is found to be critical: when interactions between nascent chains are inhibited or delayed, they become trapped in stable misfolded states that are no longer assembly-competent. Conversely, early interactions allow the two nascent chains to nucleate native-like quaternary structures that grow in size and stability as translation advances. We conjecture that protein folding mechanisms enabled by ribosome cooperation are more broadly relevant to intermediate filaments and other protein classes.

Suggested Citation

  • Florian Wruck & Jaro Schmitt & Katharina Till & Kai Fenzl & Matilde Bertolini & Frank Tippmann & Alexandros Katranidis & Bernd Bukau & Günter Kramer & Sander J. Tans, 2025. "Co-translational ribosome pairing enables native assembly of misfolding-prone subunits," Nature Communications, Nature, vol. 16(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61500-y
    DOI: 10.1038/s41467-025-61500-y
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    References listed on IDEAS

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    1. Federico Cerullo & Sebastian Filbeck & Pratik Rajendra Patil & Hao-Chih Hung & Haifei Xu & Julia Vornberger & Florian W. Hofer & Jaro Schmitt & Guenter Kramer & Bernd Bukau & Kay Hofmann & Stefan Pfef, 2022. "Bacterial ribosome collision sensing by a MutS DNA repair ATPase paralogue," Nature, Nature, vol. 603(7901), pages 509-514, March.
    2. Ivanka Kamenova & Pooja Mukherjee & Sascha Conic & Florian Mueller & Farrah El-Saafin & Paul Bardot & Jean-Marie Garnier & Doulaye Dembele & Simona Capponi & H. T. Marc Timmers & Stéphane D. Vincent &, 2019. "Co-translational assembly of mammalian nuclear multisubunit complexes," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Jinsook Ahn & Inseong Jo & So-mi Kang & Seokho Hong & Suhyeon Kim & Soyeon Jeong & Yong-Hak Kim & Bum-Joon Park & Nam-Chul Ha, 2019. "Structural basis for lamin assembly at the molecular level," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    4. Ayala Shiber & Kristina Döring & Ulrike Friedrich & Kevin Klann & Dorina Merker & Mostafa Zedan & Frank Tippmann & Günter Kramer & Bernd Bukau, 2018. "Cotranslational assembly of protein complexes in eukaryotes revealed by ribosome profiling," Nature, Nature, vol. 561(7722), pages 268-272, September.
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