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

Florian Wruck, Jaro Schmitt, Katharina Till, Kai Fenzl, Matilde Bertolini, Frank Tippmann, Alexandros Katranidis, Bernd Bukau, Günter Kramer and Sander J. Tans ()
Additional contact information
Florian Wruck: AMOLF
Jaro Schmitt: DKFZ-ZMBH Alliance
Katharina Till: AMOLF
Kai Fenzl: DKFZ-ZMBH Alliance
Matilde Bertolini: DKFZ-ZMBH Alliance
Frank Tippmann: DKFZ-ZMBH Alliance
Alexandros Katranidis: Forschungszentrum Jülich (FZJ)
Bernd Bukau: DKFZ-ZMBH Alliance
Günter Kramer: DKFZ-ZMBH Alliance
Sander J. Tans: AMOLF

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-61500-y

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