The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons
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Authors
Koren, Itay
Timms, Richard T
Kula, Tomasz
Xu, Qikai
Li, Mamie Z
Elledge, Stephen J
Publication Date
2018-06Journal Title
Cell
ISSN
0092-8674
Publisher
Elsevier
Volume
173
Issue
7
Pages
1622-1635.e14
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Koren, I., Timms, R. T., Kula, T., Xu, Q., Li, M. Z., & Elledge, S. J. (2018). The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons. Cell, 173 (7), 1622-1635.e14. https://doi.org/10.1016/j.cell.2018.04.028
Abstract
Degrons are minimal elements that mediate the interaction of proteins with degradation machineries to promote proteolysis. Despite their central role in proteostasis, the number of known degrons remains small and a facile technology to characterize them is lacking. Using a strategy combining Global Protein Stability (GPS) profiling with a synthetic human peptidome, we identify thousands of peptides containing degron activity. Using CRISPR screening, we established that the stability of many proteins is regulated through degrons located at their C-terminus. We characterize eight Cullin-RING E3 ubiquitin ligase (CRL) complexes adaptors that regulate C-terminal degrons including six CRL2 and two CRL4 complexes and computationally implicate multiple non-CRLs in end recognition. Human proteome analysis revealed that the C-termini of eukaryotic proteins are depleted for C-terminal degrons, suggesting an E3 ligase-dependent modulation of proteome composition. Thus, we propose that a series of ‘C-end rules’ operate to govern protein stability and shape the eukaryotic proteome.
Keywords
C terminus, CRL, Cullin, DesCEND, E3 ubiquitin ligase, GPS, degron, global protein stability, protein degradation, ubiquitination, Amino Acid Motifs, Animals, Antigens, Neoplasm, CRISPR-Cas Systems, Computational Biology, Genetic Vectors, HEK293 Cells, Humans, Lentivirus, Leupeptins, Open Reading Frames, Peptides, Proteasome Endopeptidase Complex, Protein Stability, Protein Subunits, Proteolysis, Proteome, Receptors, Cytokine, Ubiquitin-Protein Ligases
Sponsorship
Wellcome Trust (201387/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1016/j.cell.2018.04.028
This record's URL: https://www.repository.cam.ac.uk/handle/1810/286593
Rights
Licence:
http://creativecommons.org/licenses/by-nc-nd/4.0/
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