Attachment of ubiquitin to proteins is catalyzed by a family of ubiquitin-conjugating (UBC) enzymes. Although these enzymes are essential for many cellular processes; their molecular functions remain unclear because no physiological target has been identified for any of them. Here we show that four UBC proteins (UBC4, UBC5, UBC6, and UBC7) target the yeast MAT alpha 2 transcriptional regulator for intracellular degradation by two distinct ubiquitination pathways. UBC6 and UBC7 define one of the pathways and can physically associate. The UBC6/UBC7-containing complex targets the Deg1 degradation signal of alpha 2, a conclusion underscored by the finding that UBC6 is encoded by DOA2, a gene previously implicated in Deg1-mediated degradation. These data reveal an unexpected overlap in substrate specificity among diverse UBC enzymes and suggest a combinatorial mechanism of substrate selection in which UBC enzymes partition into multiple ubiquitination complexes.
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