Fine-tunning of ubiquitin-conjugating enzymes (E2s), which orchestrate posttranslational modifications that control protein and cell fate, remains largely elusive. Recently, copper signaling emerged as a critical regulator of cell growth and neuronal differentiation, yet confluence of these key pathways has not been reported. Here we show that subtle rises in cellular copper strikingly increase polyubiquitination in numerous mammalian cell lines, while markedly accelerating protein degradation. Using biochemistry, proteomics, NMR spectroscopy and mutational analyses, we link Cu+-enhanced protein ubiquitination and degradation to an evolutionarily conserved CXXXC motif in the E2D (UBE2D) clade. Cu+ binding to this sub-femtomolar-affinity site induces allosteric changes that transduce to the active site region and increase enzyme activity. This machinery couples physiologic fluctuations in cytoplasmic Cu+ with the degradation rate of numerous proteins including the canonical substrate, p53. In Drosophila harboring a larval-lethal UbcD1 knockdown, human E2D2 expression supported near-normal development but ablation of its Cu+ binding site profoundly disrupted head development. Our findings introduce Cu+ as a novel regulator of E2D activity through an allosteric switch whose emergence coincided with animal multicellularity. Through this unexpected signaling mechanism, crosstalk between copper and protein ubiquitination could have broad impact including upon neurobiological development and cell cycling.