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Cotranslational assembly of protein complexes in eukaryotes revealed by ribosome profiling

Author

Listed:
  • Ayala Shiber

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Kristina Döring

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Ulrike Friedrich

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Kevin Klann

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Dorina Merker

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Mostafa Zedan

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Frank Tippmann

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Günter Kramer

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

  • Bernd Bukau

    (Center for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance
    German Cancer Research Center (DKFZ))

Abstract

The folding of newly synthesized proteins to the native state is a major challenge within the crowded cellular environment, as non-productive interactions can lead to misfolding, aggregation and degradation1. Cells cope with this challenge by coupling synthesis with polypeptide folding and by using molecular chaperones to safeguard folding cotranslationally2. However, although most of the cellular proteome forms oligomeric assemblies3, little is known about the final step of folding: the assembly of polypeptides into complexes. In prokaryotes, a proof-of-concept study showed that the assembly of heterodimeric luciferase is an organized cotranslational process that is facilitated by spatially confined translation of the subunits encoded on a polycistronic mRNA4. In eukaryotes, however, fundamental differences—such as the rarity of polycistronic mRNAs and different chaperone constellations—raise the question of whether assembly is also coordinated with translation. Here we provide a systematic and mechanistic analysis of the assembly of protein complexes in eukaryotes using ribosome profiling. We determined the in vivo interactions of the nascent subunits from twelve hetero-oligomeric protein complexes of Saccharomyces cerevisiae at near-residue resolution. We find nine complexes assemble cotranslationally; the three complexes that do not show cotranslational interactions are regulated by dedicated assembly chaperones5–7. Cotranslational assembly often occurs uni-directionally, with one fully synthesized subunit engaging its nascent partner subunit, thereby counteracting its propensity for aggregation. The onset of cotranslational subunit association coincides directly with the full exposure of the nascent interaction domain at the ribosomal tunnel exit. The action of the ribosome-associated Hsp70 chaperone Ssb8 is coordinated with assembly. Ssb transiently engages partially synthesized interaction domains and then dissociates before the onset of partner subunit association, presumably to prevent premature assembly interactions. Our study shows that cotranslational subunit association is a prevalent mechanism for the assembly of hetero-oligomers in yeast and indicates that translation, folding and the assembly of protein complexes are integrated processes in eukaryotes.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:nature:v:561:y:2018:i:7722:d:10.1038_s41586-018-0462-y
    DOI: 10.1038/s41586-018-0462-y
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    Citations

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    Cited by:

    1. Johannes Venezian & Hagit Bar-Yosef & Hila Ben-Arie Zilberman & Noam Cohen & Oded Kleifeld & Juan Fernandez-Recio & Fabian Glaser & Ayala Shiber, 2024. "Diverging co-translational protein complex assembly pathways are governed by interface energy distribution," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Maximilian Seidel & Anja Becker & Filipa Pereira & Jonathan J. M. Landry & Nayara Trevisan Doimo Azevedo & Claudia M. Fusco & Eva Kaindl & Natalie Romanov & Janina Baumbach & Julian D. Langer & Erin M, 2022. "Co-translational assembly orchestrates competing biogenesis pathways," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Phillip C. Burke & Heungwon Park & Arvind Rasi Subramaniam, 2022. "A nascent peptide code for translational control of mRNA stability in human cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Maximilian Seidel & Natalie Romanov & Agnieszka Obarska-Kosinska & Anja Becker & Nayara Trevisan Doimo de Azevedo & Jan Provaznik & Sankarshana R. Nagaraja & Jonathan J. M. Landry & Vladimir Benes & M, 2023. "Co-translational binding of importins to nascent proteins," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Bayan Mashahreh & Shir Armony & Kristoffer Enøe Johansson & Alon Chappleboim & Nir Friedman & Richard G. Gardner & Rasmus Hartmann-Petersen & Kresten Lindorff-Larsen & Tommer Ravid, 2022. "Conserved degronome features governing quality control associated proteolysis," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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