title: FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors.
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: Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA.
authors: Anna C
authors: AC
authors: Calkin
authors: Benjamin T
authors: BT
authors: Goult
authors: Li
authors: L
authors: Zhang
authors: Louise
authors: L
authors: Fairall
authors: Cynthia
authors: C
authors: Hong
authors: John W R
authors: JW
authors: Schwabe
authors: Peter
authors: P
authors: Tontonoz
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D018110:Receptors, Lipoprotein / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000596:Amino Acids; D018110:Receptors, Lipoprotein; C542022:Mylip protein, mouse; D044767:Ubiquitin-Protein Ligases