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Peer-reviewedCC BY 4.0Nature Communications

Quasi-continuous cotranslational compaction and folding of a multidomain protein

  • Spyridoula Mitsikosta1
  • Justin M Westerfield1
  • Fátima Pardo-Avila2
  • Michael Levitt2
  • Gunnar von Heijne3,4
  • Ane Metola5
5 affiliations
  1. 1Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
  2. 2Department of Structural Biology, Stanford University, Palo Alto, CA, USA.
  3. 3Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. [email protected].
  4. 4Science for Life Laboratory Stockholm University, Box 1031, Solna, Sweden. [email protected].
  5. 5Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. [email protected].
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Abstract

Most proteins start to fold cotranslationally as they come off the ribosome. So far, studies of cotranslational folding have focused mainly on small, single-domain proteins. Here, we have used Force Profile Analysis to study the cotranslational folding of Firefly Luciferase, a complex 550-residue protein composed of an N-terminal domain (NTD) encompassing two split Rossmann folds (RF-1, RF-2) and a β-roll, and a flexibly attached C-terminal domain (CTD). The folding process is characterized by a quasi-continuous series of compaction/folding steps that generate intermediate-size pulling forces on the nascent chain, punctuated by a prominent high-force event that represents the folding of the RF-2 domain, and a few low-force instances that likely indicate the formation of distinct folding intermediates. Trigger Factor interacts extensively with the nascent chain when the central part of RF-2 and the early parts of the CTD are synthesized. Our analysis uncovers a cotranslational compaction/folding process that is rich in detail and not just a simple succession of a few distinct, cooperative folding transitions.

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Cite

BibTeXRIS
BibTeX
@article{mitsikosta2026quasicontinuous,
  title = {{Quasi-continuous cotranslational compaction and folding of a multidomain protein}},
  author = {Spyridoula Mitsikosta and Justin M Westerfield and Fátima Pardo-Avila and Michael Levitt and Gunnar von Heijne and Ane Metola},
  journal = {Nature Communications},
  year = {2026},
  month = oct,
  doi = {10.1038/s41467-026-78090-y},
  url = {https://www.nature.com/articles/s41467-026-78090-y},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Quasi-continuous cotranslational compaction and folding of a multidomain protein
AU  - Spyridoula Mitsikosta
AU  - Justin M Westerfield
AU  - Fátima Pardo-Avila
AU  - Michael Levitt
AU  - Gunnar von Heijne
AU  - Ane Metola
PY  - 2026
DA  - 2026/10/05
JO  - Nature Communications
DO  - 10.1038/s41467-026-78090-y
UR  - https://www.nature.com/articles/s41467-026-78090-y
AB  - Most proteins start to fold cotranslationally as they come off the ribosome. So far, studies of cotranslational folding have focused mainly on small, single-domain proteins. Here, we have used Force Profile Analysis to study the cotranslational folding of Firefly Luciferase, a complex 550-residue protein composed of an N-terminal domain (NTD) encompassing two split Rossmann folds (RF-1, RF-2) and a β-roll, and a flexibly attached C-terminal domain (CTD). The folding process is characterized by a quasi-continuous series of compaction/folding steps that generate intermediate-size pulling forces on the nascent chain, punctuated by a prominent high-force event that represents the folding of the RF-2 domain, and a few low-force instances that likely indicate the formation of distinct folding intermediates. Trigger Factor interacts extensively with the nascent chain when the central part of RF-2 and the early parts of the CTD are synthesized. Our analysis uncovers a cotranslational compaction/folding process that is rich in detail and not just a simple succession of a few distinct, cooperative folding transitions.
SN  - 2041-1723
ER  -