TY - JOUR
T1 - Recognition of substrate degrons by E3 ubiquitin ligases and modulation by small-molecule mimicry strategies
AU - Lucas, Xavier
AU - Ciulli, Alessio
N1 - European Research Council (ERC-2012-StG-311460DrugE3CRLs Starting Grant to A.C.); the European Commission (H2020-MSCA-IF-2015-806323 Marie Skłodowska-Curie Actions Individual Fellowship to X.L.); and the Wellcome Trust (Strategic Awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to the Division of Biological Chemistry and Drug Discovery at Dundee).
PY - 2017/6
Y1 - 2017/6
N2 - 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).
AB - 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).
U2 - 10.1016/j.sbi.2016.12.015
DO - 10.1016/j.sbi.2016.12.015
M3 - Review article
C2 - 28130986
SN - 0959-440X
VL - 44
SP - 101
EP - 110
JO - Current Opinion in Structural Biology
JF - Current Opinion in Structural Biology
ER -