Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/26701
Title: FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors.
Authors: Calkin, AC
Goult, BT
Zhang, L
Fairall, L
Hong, C
Schwabe, JW
Tontonoz, P
First Published: 13-Dec-2011
Citation: PROC NATL ACAD SCI U S A, 2011, 108 (50), pp. 20107-20112
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.
DOI Link: 10.1073/pnas.1111589108
eISSN: 1091-6490
Links: http://hdl.handle.net/2381/26701
Type: Journal Article
Appears in Collections:Published Articles, Dept. of Biochemistry

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