The eukaryotic ubiquitin system regulates essential cell events such as DNA repair, protein homeostasis, and signal transduction. Like many biochemical processes, ubiquitination must ensure signaling efficiency and in the meantime maintain substrate specificity. We examine this signal-specificity relationship by theoretical models of polyubiquitinations that tag proteins for the proteasomal degradation. Parsimonious models provide explicit formulas to key measurable quantities and offer guiding

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... insights into the signal-specificity tradeoffs under varying structures and kinetics. Models with measured kinetics from two primary cell-cycle ligases (SCF and APC) explain mechanisms of chain initiation, elongation slowdown, chain-length dependence of E3-substrate affinity, and deubiquitinases. We find that substrate discrimination over ubiquitin transfer rates is consistently more efficient than over substrate-E3 ligase binding energy, regardless of circuit structure, parameter value, and dynamics. E3-associated substrate deubiquitination increases the discrimination over the former and in the meantime decreases the latter, further widening their difference. Both discrimination strategies might be simultaneously explored by an E3 system to effectively proofread substrates as we demonstrated by analyzing experimental data from the CD4-Vpu-SCF system. We also identify that sequential deubiquitination circuit may act as a specificity switch, by which a modest change in deubiquitination and/or processivity can greatly increase substrate discrimination without much compromise in degradation signal. This property may be utilized as a gatekeeper mechanism to direct a temporal polyubiquitination and thus degradation order of substrates with small biochemical differences.