A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation

Abstract

The N-terminal residue influences protein stability through N-end rule pathways. Here, through stability profiling of the human N-terminome, we uncover multiple new features of the N-end rule. In addition to uncovering new specificities of UBR E3 ligases, we characterize two related Cullin-RING E3 ligase complexes, Cul2 ^ZYG11B and CUL2 ^ZER1, that act redundantly to target N-terminal glycine. N-terminal glycine degrons are depleted at native N-termini but strongly enriched at caspase cleavage sites, suggesting roles for the substrate adaptors ZYG11B and ZER1 in protein degradation during apoptosis. Furthermore, ZYG11B and ZER1 participate in the quality control of N-myristoylated proteins, wherein N-terminal glycine degrons are conditionally exposed following a failure of N-myristoylation. Thus, an additional N-end rule pathway specific for glycine regulates the stability of metazoan proteomes.