A global, integrated view of the ubiquitylation site occupancy and dynamics

Author:

Prus Gabriela,Satpathy Shankha,Weinert Brian T.,Narita Takeo,Choudhary ChunaramORCID

Abstract

SummaryUbiquitylation regulates virtually all proteins and biological processes in a cell. However, the global site-specific occupancy (stoichiometry) and turnover rate of ubiquitylation have never been quantified. Here, we present the first integrated picture of ubiquitylation site occupancy and half-life. Ubiquitylation occupancy spans four orders of magnitude, but the median ubiquitylation site occupancy is three orders of magnitude lower than that of phosphorylation. The occupancy, turnover rate, and the regulation of sites by proteasome inhibitors show strong interrelationships. These properties can discriminate signaling-relevant sites from the sites involved in proteasomal degradation. The sites strongly upregulated by proteasome inhibitors have a longer half-life, and the half-life increases with increasing protein length. Importantly, a previously unknown surveillance mechanism rapidly deubiquitylates all ubiquitin-specific E1 and E2 enzymes and protects them against bystander ubiquitylation accumulation. This work reveals general principles of ubiquitylation-dependent governance and offers conceptual insights into the dynamic regulation of the cell.HighlightsUbiquitylation site occupancy is 3 orders of magnitude lower than phosphorylationThe highest 80% and the lowest 20% occupancy sites have distinct propertiesHigh occupancy sites are concentrated in the cytoplasmic domains of SLC proteinsA dedicated mechanism prevevents ubiquitylation accumulation in E1s and E2s

Publisher

Cold Spring Harbor Laboratory

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