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N-degron and C-degron pathways of protein degradation
Open accessAbstract
This perspective is partly review and partly proposal. N-degrons and C-degrons are degradation signals whose main determinants are, respectively, the N-terminal and C-terminal residues of cellular proteins. N-degrons and C-degrons include, to varying extents, adjoining sequence motifs, and also internal lysine residues that function as polyubiquitylation sites. Discovered in 1986, N-degrons were the first degradation signals in short-lived proteins. A particularly large set of C-degrons was discovered in 2018. We describe multifunctional proteolytic systems that target N-degrons and C-degrons. We also propose to denote these systems as “N-degron pathways” and “C-degron pathways.” The former notation replaces the earlier name “N-end rule pathways.” The term “N-end rule” was introduced 33 years ago, when only some N-terminal residues were thought to be destabilizing. However, studies over the last three decades have shown that all 20 amino acids of the genetic code can act, in cognate sequence contexts, as destabilizing N-terminal residues. Advantages of the proposed terms include their brevity and semantic uniformity for N-degrons and C-degrons. In addition to being topologically analogous, N-degrons and C-degrons are related functionally. A proteolytic cleavage of a subunit in a multisubunit complex can create, at the same time, an N-degron (in a C-terminal fragment) and a spatially adjacent C-degron (in an N-terminal fragment). Consequently, both fragments of a subunit can be selectively destroyed through attacks by the N-degron and C-degron pathways.
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“Additionally, MHC class I loading might be enhanced by the cytosolic, C-terminal E5 degron, which has been described to increase protein turnover and proteasomal degradation in the cytosol [30].”
From Preclinical development of an mRNA-based multiepitope immunotherapeutic for glioblastoma (2025) · cites this paper as [30]
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Metadata
- Authors
- Varshavsky, A.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Varshavsky, Alexander
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-01-07
- Volume
- 116
- Issue
- 2
- Pages
- 358-366
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6329975
- OpenAlex
- W2910161842
- Cited by
- 544
- References
- 82
- Citations by year
- 2026: 52 · 2025: 71 · 2024: 79 · 2023: 84 · 2022: 77 · 2021: 77 · 2020: 68 · 2019: 36
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- HHS | National Institutes of Health (DK039520, GM031530)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- N-degron, protein degradation, N-end rule, protein destabilization, polyubiquitination, proteolytic pathways, short-lived proteins, protein quality control
- MeSH terms
- Protein Domains, Amino Acid Sequence, Animals, Humans, Amino Acid Motifs, Proteolysis
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