An unstructured initiation site is required for efficient proteasome-mediated degradation
Abstract
The proteasome is the main ATP-dependent protease in eukaryotic cells and controls the concentration of many regulatory proteins in the cytosol and nucleus. Proteins are targeted to the proteasome by the covalent attachment of polyubiquitin chains. The ubiquitin modification serves as the proteasome recognition element but by itself is not sufficient for efficient degradation of folded proteins. We report that proteolysis of tightly folded proteins is accelerated greatly when an unstructured region is attached to the substrate. The unstructured region serves as the initiation site for degradation and is hydrolyzed first, after which the rest of the protein is digested sequentially. These results identify the initiation site as a novel component of the targeting signal, which is required to engage the proteasome unfolding machinery efficiently. The proteasome degrades a substrate by first binding to its ubiquitin modification and then initiating unfolding at an unstructured region.
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β-catenin proteins undergo proteasomal destruction, which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal.
“Next, the β-catenin proteins undergo proteasomal destruction [259, 260], which is greatly accelerated by the presence of IDRs in addition to the bound ubiquitin signal [262].”
From Intrinsically disordered proteins play diverse roles in cell signaling (2022) · cites this paper as [262]
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Self-citation
- Authors
- Prakash, S., Tian, L., Ratliff, K. S., Lehotzky, R. E., & Matouschek, A.
- Affiliations
- Northwestern University (US)
- Corresponding author
- Matouschek, Andreas
- Venue
- Nature Structural & Molecular Biology
- Published
- 2004-08-15
- Volume
- 11
- Issue
- 9
- Pages
- 830-837
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2069494008
- Cited by
- 458
- References
- 56
- Citations by year
- 2026: 19 · 2025: 17 · 2024: 14 · 2023: 14 · 2022: 15 · 2021: 33 · 2020: 26 · 2019: 22 · 2018: 13 · 2017: 24 · 2016: 23 · 2015: 19 · 2014: 15 · 2013: 26 · 2012: 17
- FWCI
- 7.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM63004, R01GM063004)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- proteasome, protein degradation, unstructured regions, initiation sites, polyubiquitin chains, protein unfolding, ATP-dependent proteolysis, protein folding
- MeSH terms
- Adenosine Triphosphate, Animals, Bacillus, Binding Sites, Catalysis, Cell Nucleus, Cysteine Endopeptidases, Cytosol, Electrophoresis, Polyacrylamide Gel, Escherichia coli, Hydrolysis, Models, Biological, Multienzyme Complexes, Endopeptidases, Promoter Regions, Genetic, Protein Binding, Rabbits, Temperature, Time Factors, Protein Structure, Tertiary, Protein Folding, Ubiquitin, Proteasome Endopeptidase Complex
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