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

Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):20107-12. doi: 10.1073/pnas.1111589108. Epub 2011 Nov 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Amino Acids
  • Animals
  • Cell Membrane / metabolism
  • Conserved Sequence
  • HEK293 Cells
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Stability
  • Protein Structure, Tertiary
  • Proteolysis*
  • Receptors, Lipoprotein / chemistry
  • Receptors, Lipoprotein / metabolism*
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination

Substances

  • Amino Acids
  • Receptors, Lipoprotein
  • Mylip protein, mouse
  • Ubiquitin-Protein Ligases