Protein Synthesis in the Developing Neocortex at Near-Atomic Resolution Reveals Ebp1-Mediated Neuronal Proteostasis at the 60S Tunnel Exit
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Abstract
Protein synthesis must be finely tuned in the developing nervous system as the final essential step of gene expression. This study investigates the architecture of ribosomes from the neocortex during neurogenesis, revealing Ebp1 as a high-occupancy 60S peptide tunnel exit (TE) factor during protein synthesis at near-atomic resolution by cryoelectron microscopy (cryo-EM). Ribosome profiling demonstrated Ebp1-60S binding is highest during start codon initiation and N-terminal peptide elongation, regulating ribosome occupancy of these codons. Membrane-targeting domains emerging from the 60S tunnel, which recruit SRP/Sec61 to the shared binding site, displace Ebp1. Ebp1 is particularly abundant in the early-born neural stem cell (NSC) lineage and regulates neuronal morphology. Ebp1 especially impacts the synthesis of membrane-targeted cell adhesion molecules (CAMs), measured by pulsed stable isotope labeling by amino acids in cell culture (pSILAC)/bioorthogonal noncanonical amino acid tagging (BONCAT) mass spectrometry (MS). Therefore, Ebp1 is a central component of protein synthesis, and the ribosome TE is a focal point of gene expression control in the molecular specification of neuronal morphology during development.
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- Authors
- Kraushar, M. L., Krupp, F., Harnett, D., Turko, P., Ambrozkiewicz, M. C., Sprink, T., Imami, K., Günnigmann, M., Zinnall, U., Vieira-Vieira, C. H., Schaub, T., Münster-Wandowski, A., Bürger, J., Borisova, E., Yamamoto, H., Rasin, M.-R., Ohler, U., Beule, D., Mielke, T., Tarabykin, V., Landthaler, M., Kramer, G., Vida, I., Selbach, M., & Spahn, C. M. T.
- Affiliations
- Charité – Universitätsmedizin Berlin (DE)
- Max Delbrück Center (DE)
- Humboldt-Universität zu Berlin (DE)
- German Cancer Research Center (DE)
- Max Planck Institute for Molecular Genetics (DE)
- N. I. Lobachevsky State University of Nizhny Novgorod (RU)
- Corresponding author
- Kraushar, Matthew L.
- Spahn, Christian M.T.
- ORCID
- Kraushar, Matthew L.
- Krupp, Ferdinand
- Harnett, Dermot
- Turko, Paul
- Ambrozkiewicz, Mateusz C.
- Sprink, Thiemo
- Imami, Koshi
- Günnigmann, Manuel
- Zinnall, Ulrike
- Vieira-Vieira, Carlos H.
- Schaub, Theres
- Bürger, Jörg
- Borisova, Ekaterina
- Yamamoto, Hiroshi
- Ohler, Uwe
- Beule, Dieter
- Mielke, Thorsten
- Tarabykin, Victor
- Landthaler, Markus
- Vida, Imre
- Selbach, Matthias
- Spahn, Christian M.T.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 81
- Issue
- 2
- Pages
- 304-322.e16
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC8163098
- OpenAlex
- W3117323852
- Cited by
- 49
- References
- 9
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 14 · 2023: 8 · 2022: 7 · 2021: 4 · 2020: 2
- FWCI
- 1.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- European Molecular Biology Organization (190-2016)
- Russian Science Foundation (19-14-00345)
- European Research Council (743118)
- Deutsche Forschungsgemeinschaft (EXC 257, SFB-958, SFB-740)
- European Molecular Biology Laboratory
- Alexander von Humboldt-Stiftung
- National Institutes of Health (1F30MH106220)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- Ebp1, ribosome profiling, protein synthesis, neocortex development, neurogenesis, neuronal proteostasis, adhesion molecules, neural stem cells, neuronal morphology, ribosome occupancy
- MeSH terms
- Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Proteostasis, Animals, Animals, Newborn, Binding Sites, DNA-Binding Proteins, Embryo, Mammalian, Female, Male, Neurons, Protein Binding, Protein Biosynthesis, Cell Adhesion Molecules, Neuronal, RNA-Binding Proteins, Signal Recognition Particle, Gene Expression Regulation, Developmental, Neocortex, Cryoelectron Microscopy, Cell Line, Tumor, Mice, Ribosome Subunits, Large, Eukaryotic, Protein Interaction Domains and Motifs, Neurogenesis, Neural Stem Cells, Primary Cell Culture
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