C-mannosylation supports folding and enhances stability of thrombospondin repeats
Open accessAbstract
Previous studies demonstrated importance of C-mannosylation for efficient protein secretion. To study its impact on protein folding and stability, we analyzed both C-mannosylated and non-C-mannosylated thrombospondin type 1 repeats (TSRs) of netrin receptor UNC-5. In absence of C-mannosylation, UNC-5 TSRs could only be obtained at low temperature and a significant proportion displayed incorrect intermolecular disulfide bridging, which was hardly observed when C-mannosylated. Glycosylated TSRs exhibited higher resistance to thermal and reductive denaturation processes, and the presence of C-mannoses promoted the oxidative folding of a reduced and denatured TSR in vitro. Molecular dynamics simulations supported the experimental studies and showed that C-mannoses can be involved in intramolecular hydrogen bonding and limit the flexibility of the TSR tryptophan-arginine ladder. We propose that in the endoplasmic reticulum folding process, C-mannoses orient the underlying tryptophan residues and facilitate the formation of the tryptophan-arginine ladder, thereby influencing the positioning of cysteines and disulfide bridging.
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- Authors
- Shcherbakova, A., Preller, M., Taft, M. H., Pujols, J., Ventura, S., Tiemann, B., Buettner, F. F., & Bakker, H.
- Affiliations
- Medizinische Hochschule Hannover (DE)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Bakker, Hans
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2019-12-23
- Volume
- 8
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC6954052
- OpenAlex
- W2995628811
- Cited by
- 85
- References
- 44
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 7 · 2023: 12 · 2022: 16 · 2021: 19 · 2020: 13 · 2019: 1 · 2018: 1
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- OPUS (Augsburg University) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (FOR2509 BA 4091/6-1, BA 4091/5-1, BU 2920/2-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- C-mannosylation, thrombospondin type 1 repeats, protein folding, protein stability, oxidative protein folding, glycosylation, thermal denaturation, intramolecular hydrogen bonding
- MeSH terms
- Animals, Arginine, Cysteine, Disulfides, Drosophila melanogaster, Endoplasmic Reticulum, Glycosylation, Hydrogen Bonding, Mannose, Membrane Proteins, Protein Conformation, Receptors, Cell Surface, Tryptophan, Caenorhabditis elegans, Protein Folding, Thrombospondins, Caenorhabditis elegans Proteins, Molecular Dynamics Simulation
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