The N-end rule pathway of targeted proteolysis, which relates the stability of a protein to the nature of its N-terminus, has emerged as a key regulator of diverse processes in eukaryotes. Recent reports that N-terminally acetylated and methionine-initiating proteins can be targeted for degradation have uncovered novel branches of the pathway, and a wide range of protein substrates has now been identified in animals, fungi, and plants. Of particular interest is the finding that the N-end rule pathway mediates oxygen and nitric oxide (NO) sensing in plants and animals by controlling the stability of kingdom-specific substrates. These findings highlight how conserved degradation mechanisms of the N-end rule pathway underlie functional divergence throughout eukaryotes.
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