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

Richard T. Timms, Zhiqian Zhang, David Y. Rhee, J. Wade Harper, Itay Koren, Stephen J. Elledge

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84 Scopus citations


The N-terminal residue influences protein stability through N-degron pathways. We used stability profiling of the human N-terminome to uncover multiple additional features of N-degron pathways. In addition to uncovering extended specificities of UBR E3 ligases, we characterized two related Cullin-RING E3 ligase complexes, Cul2ZYG11B and Cul2ZER1, 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 were found to participate in the quality control of N-myristoylated proteins, in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation. Thus, an additional N-degron pathway specific for glycine regulates the stability of metazoan proteomes.

Original languageEnglish
Article numbereaaw4912
Issue number6448
StatePublished - 2019

Bibliographical note

Funding Information:
R.T.T. is a Sir Henry Wellcome Postdoctoral Fellow (201387/Z/16/Z). Z.Z. is a Croucher Foundation Honorary Ph.D. Scholar. This work was supported by an NIH grant (AG11085) to S.J.E. and J.W.H.; S.J.E. is an investigator with the Howard Hughes Medical Institute.

Publisher Copyright:
2017 © The Authors,


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