FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors

Calkin, Anna C and Goult, Benjamin T and Zhang, Li and Fairall, Louise and Hong, Cynthia and Schwabe, John W R and Tontonoz, Peter (2011) FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proceedings of the National Academy of Sciences of the United States of America, 108 (50). pp. 20107-20112. ISSN 1091-6490. (doi:https://doi.org/10.1073/pnas.1111589108) (The full text of this publication is not currently available from this repository. You may be able to access a copy if URLs are provided)

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Official URL
http://dx.doi.org/10.1073/pnas.1111589108

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.

Item Type: Article
Subjects: Q Science > QH Natural history > QH301 Biology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Ben Goult
Date Deposited: 07 Aug 2014 16:08 UTC
Last Modified: 25 Mar 2015 16:37 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/42117 (The current URI for this page, for reference purposes)
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