title: Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies.
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, for example, proteolysis-targeting chimeras (PROTACs).
authors.affiliation: School of Life Sciences, University of Dundee, Division of Biological Chemistry and Drug Discovery, James Black Centre, Dow Street, Dundee DD1 5EH, UK.
authors.forename: Xavier
authors.initials: X
authors.lastname: Lucas
authors.affiliation: School of Life Sciences, University of Dundee, Division of Biological Chemistry and Drug Discovery, James Black Centre, Dow Street, Dundee DD1 5EH, UK. Electronic address: a.ciulli@dundee.ac.uk.
authors.forename: Alessio
authors.initials: A
authors.lastname: Ciulli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D054852:Small Molecule Libraries; D044767:Ubiquitin-Protein Ligases