Being targeted for polyubiquitylation often means the end of life for the substrate protein. In this issue of Molecular Cell, Ouni et al. (2010) demonstrate that the yeast transcription factor Met4, a target of the SCF(Met30) E3 ligase for nonproteolytic polyubiquitylation, can also function to target its cofactors for proteolytic ubiquitylation by the same E3 ligase.
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