ArticleProceedings of the National Academy of Sciences of the United States of America2019
Energetic dependencies dictate folding mechanism in a complex protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Quasi-continuous cotranslational compaction and folding of a multidomain protein.Nature communications · 2026Article
- Single-molecule dissection of CFTR folding defects and pharmacological rescue.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Force writes memory: proline isomerization as a molecular memory switch.Biochemical Society transactions · 2025Review
- The human ribosome modulates multidomain protein biogenesis by delaying cotranslational domain docking.Nature structural & molecular biology · 2025Article
- Arrest Peptide Profiling resolves co-translational folding pathways and chaperone interactions in vivo.Nature communications · 2025Article
- On the free energy of protein folding in optical tweezers experiments.Biophysical reviews · 2025Review
- Parsing digital or analog TCR performance through piconewton forces.Science advances · 2024Article
- AutoRNC: An automated modeling program for building atomic models of ribosome-nascent chain complexes.Structure (London, England : 1993) · 2024Article
- Retracing the evolution of a modern periplasmic binding protein.Protein science : a publication of the Protein Society · 2023Article
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- The cofactor-dependent folding mechanism of Drosophila cryptochrome revealed by single-molecule pulling experiments.Nature communications · 2023Article
- A Generalized Transformer-Based Pulse Detection Algorithm.ACS sensors · 2022Article
- Mechanical regulation of talin through binding and history-dependent unfolding.Science advances · 2022Article
- Using Optical Tweezers to Monitor Allosteric Signals Through Changes in Folding Energy Landscapes.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Co-Translational Folding of Multi-Domain Proteins.Frontiers in molecular biosciences · 2022Review
- Slowest-first protein translation scheme: Structural asymmetry and co-translational folding.Biophysical journal · 2021Article
- Force Dependence of Proteins' Transition State Position and the Bell-Evans Model.Nanomaterials (Basel, Switzerland) · 2021Article
- Facile tethering of stable and unstable proteins for optical tweezers experiments.Biophysical journal · 2021Article
- Co-translational folding of nascent polypeptides: Multi-layered mechanisms for the efficient biogenesis of functional proteins.BioEssays : news and reviews in molecular, cellular and developmental biology · 2021Article
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3 authors.
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Abstract
Large proteins with multiple domains are thought to fold cotranslationally to minimize interdomain misfolding. Once folded, domains interact with each other through the formation of extensive interfaces that are important for protein stability and function. However, multidomain protein folding and the energetics of domain interactions remain poorly understood. In elongation factor G (EF-G), a highly conserved protein composed of 5 domains, the 2 N-terminal domains form a stably structured unit cotranslationally. Using single-molecule optical tweezers, we have defined the steps leading to fully folded EF-G. We find that the central domain III of EF-G is highly dynamic and does not fold upon emerging from the ribosome. Surprisingly, a large interface with the N-terminal domains does not contribute to the stability of domain III. Instead, it requires interactions with its folded C-terminal neighbors to be stably structured. Because of the directionality of protein synthesis, this energetic dependency of domain III on its C-terminal neighbors disrupts cotranslational folding and imposes a posttranslational mechanism on the folding of the C-terminal part of EF-G. As a consequence, unfolded domains accumulate during synthesis, leading to the extensive population of misfolded species that interfere with productive folding. Domain III flexibility enables large-scale conformational transitions that are part of the EF-G functional cycle during ribosome translocation. Our results suggest that energetic tuning of domain stabilities, which is likely crucial for EF-G function, complicates the folding of this large multidomain protein.
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