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Exploring the Landscape of Ectodomain Shedding by Quantitative Protein Terminomics
Open accessPreprint — published as 10.1016/j.isci.2021.102259 · Paper page
Abstract
Ectodomain shedding is a proteolytic process that regulates the levels and functions of membrane proteins. Dysregulated shedding is linked to severe diseases, including cancer and Alzheimer’s disease. However, the exact cleavage sites of shedding substrates remain largely unknown. Here, we explore the landscape of ectodomain shedding by generating large-scale, cell-type-specific maps of shedding cleavage sites. By means of N- and C-terminal peptide enrichment and quantitative mass spectrometry, we quantified protein termini in the culture media of 10 human cell lines and identified 411 cleavage sites on the ectodomain of 132 membrane proteins whose proteolytic terminal fragments are downregulated in the presence of a broad-spectrum metalloprotease inhibitor. A major fraction of the presented cleavage sites was identified in a cell-type-specific manner, and mapped onto receptors, cell adhesion molecules, and protein kinases and phosphatases. We confidently identified 86 cleavage sites as metalloprotease substrates by means of knowledge-based scoring.
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How many human proteoforms are there?
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Metadata
- Authors
- Tsumagari, K., Chang, C.-H., & Ishihama, Y.
- Affiliations
- Kyoto University (JP)
- Corresponding author
- Ishihama, Yasushi
- Venue
- iScience
- Publisher
- openRxiv
- Published
- 2020-09-24
- Volume
- 24
- Issue
- 4
- Pages
- 102259-102259
- ISSN
- 2589-0042 (ISSN-L)
- PMC
- PMC7995609
- OpenAlex
- W3135620441
- Cited by
- 24
- References
- 1
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 1 · 2021: 5
- FWCI
- 1.59
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- iScience (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion, cc-by-nc-nd)
- Funders
- Japan Society for the Promotion of Science (17H05667, CREST, 18070870)
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology (18070870)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- ectodomain shedding, cleavage site, membrane proteins, metalloproteinases, adhesion molecules, protein kinases, phosphatase, protease inhibitors, Alzheimer's disease, cancer
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