Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH

Enrico Dainese, Gianni De Fabritiis, Annalaura Sabatucci, Sergio Oddi, Clotilde Beatrice Angelucci, Chiara Di Pancrazio, Toni Giorgino, Nathaniel Stanley, Michele Del Carlo, Benjamin F. Cravatt, Mauro Maccarrone

Research output: Contribution to journalArticlepeer-review

Abstract

Lipid composition is expected to play an important role in modulating membrane enzyme activity, in particular if the substrates are themselves lipid molecules. A paradigmatic case is FAAH (fatty acid amide hydrolase), an enzyme critical in terminating endocannabinoid signalling and an important therapeutic target. In the present study, using a combined experimental and computational approach, we show that membrane lipids modulate the structure, subcellular localization and activity of FAAH.We report that the FAAHdimer is stabilized by the lipid bilayer and shows a highermembrane-binding affinity and enzymatic activity within membranes containing both cholesterol and the natural FAAH substrate AEA (anandamide). Additionally, co-localization of cholesterol, AEA and FAAH in mouse neuroblastoma cells suggests a mechanism through which cholesterol increases the substrate accessibility of FAAH.

Original languageEnglish
Pages (from-to)463-472
Number of pages10
JournalBiochemical Journal
Volume457
Issue number3
DOIs
Publication statusPublished - Feb 1 2014

Keywords

  • Cholesterol
  • Endocannabinoid
  • Fatty acid amide hydrolase (FAAH)
  • Lipid
  • Membrane

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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