The Eukaryotic Proteome Is Shaped by E3 Ubiquitin Ligases Targeting C-Terminal Degrons

• Itay Koren ^[1] ; Richard T. Timms ^[1] ; Tomasz Kula ^[1]
  1. [1] Harvard Medical School

     Harvard Medical School

     City of Boston, Estados Unidos

     
• Localización: Cell, ISSN 0092-8674, Vol. 173, Nº. 7, 2018, págs. 1622-1635
• Idioma: inglés
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• Resumen

  • 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. Employing CRISPR screening, we establish that the stability of many proteins is regulated through degrons located at their C terminus. We characterize eight Cullin-RING E3 ubiquitin ligase (CRL) complex adaptors that regulate C-terminal degrons, including six CRL2 and two CRL4 complexes, and computationally implicate multiple non-CRLs in end recognition. 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.