FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors
Year: 2011
Type: article
Abstract: The E3 ubiquitin ligase IDOL (inducible degrader of the LDL receptor) regulates LDL receptor (LDLR)-dependent cholesterol uptake, but its mechanism of action, including the molecular basis for its stringent specificity, is poorly understood. Here we show that IDOL uses a singular strategy among E3 ligases for target recognition. The IDOL FERM domain binds directly to a recognition sequence in the cytoplasmic tails of lipoprotein receptors. This physical interaction is independent of IDOL's really interesting new gene (RING) domain E3 ligase activity and its capacity for autoubiquitination. Furthermore, IDOL controls its own stability through autoubiquitination of a unique FERM subdomain fold not present in other FERM proteins. Key residues defining the IDOL-LDLR interaction and IDOL autoubiquitination are functionally conserved in their insect homologs. Finally, we demonstrate that target recognition by IDOL involves a tripartite interaction between the FERM domain, membrane phospholipids, and the lipoprotein receptor tail. Our data identify the IDOL-LDLR interaction as an evolutionarily conserved mechanism for the regulation of lipid uptake and suggest that this interaction could potentially be exploited for the pharmacologic modulation of lipid metabolism.
Authors: Anna C. Calkin, Benjamin T. Goult, Li Zhang, Louise Fairall, Cynthia Hong, John W. R. Schwabe, Peter Tontonoz
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G2083095458, Lipid and Lipoprotein Metabolism in Atherosclerosis, The molecular basis for the selective degradation of the LDL receptor by the E3 ubiquitin ligase IDOL: A potential drug target for regulating plasma cholesterol., Nuclear Receptor Signaling Pathways in Atherogenesis, G6700115685
OpenAlex ID: W2037654209