Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies

Xavier Lucas, Alessio Ciulli (Lead / Corresponding author)

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Abstract

The ubiquitin-proteasome system is a master regulator of protein homeostasis, by which proteins are initially targeted for poly-ubiquitination by E3 ligases and then degraded into short peptides by the proteasome. Nature evolved diverse peptidic motifs, termed degrons, to signal substrates for degradation. We discuss degrons of the N-end rule pathway and also degrons characterized by post-translational modifications, including phosphorylation and hydroxylation. In each case we detail the structural basis of E3 ligase:degron recognition and small-molecule mimicry approaches that disrupt those protein-protein interactions. We present as well genetic and chemical technologies that enable targeted degradation of proteins of interest, namely small-molecule dependent inducible degrons and chemical degraders, e.g. proteolysis-targeting chimeras (PROTACs).
Original languageEnglish
Pages (from-to)101-110
Number of pages10
JournalCurrent Opinion in Structural Biology
Volume44
Early online date25 Jan 2017
DOIs
Publication statusPublished - Jun 2017

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