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

Publication date: Available online 17 May 2018 Source:Cell Author(s): Itay Koren, Richard T. Timms, Tomasz Kula, Qikai Xu, Mamie Z. Li, Stephen J. Elledge 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. Graphical abstract Teaser C-terminal degron motifs regulate mammalian protein stability via interactions with Cullin-RING E3 ubiquitin ligase complexes.

Source: Cell - May 18, 2018 Category: Cytology Source Type: research