A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex
| Autor: | Sowmya Chandrasekar, Jae Ho Lee, Shu-ou Shan, Hao-Hsuan Hsieh |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Receptors Peptide Science General Physics and Astronomy Receptors Cytoplasmic and Nuclear medicine.disease_cause Ribosome General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Single-molecule biophysics Protein targeting Chaperones medicine Fluorescence Resonance Energy Transfer Biochemical reaction networks Humans lcsh:Science Receptor Signal recognition particle Protein translocation Multidisciplinary 030102 biochemistry & molecular biology biology Chemistry Endoplasmic reticulum General Chemistry Models Theoretical Recombinant Proteins Single Molecule Imaging Cell biology 030104 developmental biology Microscopy Fluorescence Chaperone (protein) Protein Biosynthesis biology.protein lcsh:Q Macromolecular crowding Ribosomes Signal Recognition Particle Biogenesis Molecular Chaperones |
| Zdroj: | Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-20 (2020) |
| ISSN: | 2041-1723 |
| Popis: | Protein biogenesis is essential in all cells and initiates when a nascent polypeptide emerges from the ribosome exit tunnel, where multiple ribosome-associated protein biogenesis factors (RPBs) direct nascent proteins to distinct fates. How distinct RPBs spatiotemporally coordinate with one another to affect accurate protein biogenesis is an emerging question. Here, we address this question by studying the role of a cotranslational chaperone, nascent polypeptide-associated complex (NAC), in regulating substrate selection by signal recognition particle (SRP), a universally conserved protein targeting machine. We show that mammalian SRP and SRP receptors (SR) are insufficient to generate the biologically required specificity for protein targeting to the endoplasmic reticulum. NAC co-binds with and remodels the conformational landscape of SRP on the ribosome to regulate its interaction kinetics with SR, thereby reducing the nonspecific targeting of signalless ribosomes and pre-emptive targeting of ribosomes with short nascent chains. Mathematical modeling demonstrates that the NAC-induced regulations of SRP activity are essential for the fidelity of cotranslational protein targeting. Our work establishes a molecular model for how NAC acts as a triage factor to prevent protein mislocalization, and demonstrates how the macromolecular crowding of RPBs at the ribosome exit site enhances the fidelity of substrate selection into individual protein biogenesis pathways. Biochemistry combined with biophysical measurements and mathematical modeling offer insight into the mechanism by which the cotranslational chaperone, nascent polypeptide-associated complex (NAC), modulates substrate selection by signal recognition particle (SRP) and reduces aberrant, nonspecific targeting of ribosomes to the ER. |
| Databáze: | OpenAIRE |
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