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

• Published in: Current opinion in structural biology Vol. 44; pp. 101 - 110
• Main Authors: Lucas, Xavier, Ciulli, Alessio
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2017
• Subjects: Amino Acid Sequence; Animals; Humans; Protein Binding - drug effects; Proteolysis - drug effects; Small Molecule Libraries - pharmacology; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2016.12.015

[Display omitted] •E3 ligases recruit substrates for proteasomal degradation by recognition of degrons.•Crystal structures reveal the structural basis and mechanism of degron recognition.•Small-molecule degron mimetics can prevent or re-direct substrate recognition.•Small-molecule inducible degrons and PROTACs enable targeted protein degradation. 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, for example, proteolysis-targeting chimeras (PROTACs).