title: Distinct functional domains contribute to degradation of the low density lipoprotein receptor (LDLR) by the E3 ubiquitin ligase inducible Degrader of the LDLR (IDOL).
abstract: We recently identified the liver X receptor-regulated E3 ubiquitin ligase inducible degrader of the LDL receptor (IDOL) as a modulator of lipoprotein metabolism. Acting as an E3 ubiquitin ligase, IDOL triggers ubiquitination and subsequent degradation of the low density lipoprotein receptor (LDLR). We demonstrate here that this outcome requires the conserved FERM and RING domains present in IDOL. The RING domain promotes ubiquitination in vitro and Lys-63-specific ubiquitination of the LDLR in vivo in response to IDOL or liver X receptor activation. We further identify RING residues that differentially influence ubiquitination of the LDLR or stability of IDOL. The FERM domain interacts with the LDLR and in living cells co-localizes with the receptor at the plasma membrane. Homology modeling revealed a phosphotyrosine-binding element embedded in the FERM domain. Mutating residues within this region or residues in the LDLR preceding the NPVY endocytosis motif abrogate LDLR degradation by IDOL. Collectively, our results indicate that both the FERM and RING domains are required for promoting lysosomal degradation of the LDLR by IDOL. Our findings may facilitate development of structure-based IDOL inhibitors aimed at increasing LDLR abundance in therapeutic strategies to treat cardiovascular disease.
authors: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Vincenzo
authors: V
authors: Sorrentino
authors: Lilith
authors: L
authors: Scheer
authors: Ana
authors: A
authors: Santos
authors: Eric
authors: E
authors: Reits
authors: Boris
authors: B
authors: Bleijlevens
authors: Noam
authors: N
authors: Zelcer
mesh_terms: D020816:Amino Acid Motifs; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D000071518:Liver X Receptors; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D054829:RING Finger Domains; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; C403126:MYLIP protein, human; D044767:Ubiquitin-Protein Ligases