TY - JOUR
T1 - Membrane lipids are key modulators of the endocannabinoid-hydrolase FAAH
AU - Dainese, Enrico
AU - De Fabritiis, Gianni
AU - Sabatucci, Annalaura
AU - Oddi, Sergio
AU - Angelucci, Clotilde Beatrice
AU - Di Pancrazio, Chiara
AU - Giorgino, Toni
AU - Stanley, Nathaniel
AU - Del Carlo, Michele
AU - Cravatt, Benjamin F.
AU - Maccarrone, Mauro
PY - 2014/2/1
Y1 - 2014/2/1
N2 - 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.
AB - 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.
KW - Cholesterol
KW - Endocannabinoid
KW - Fatty acid amide hydrolase (FAAH)
KW - Lipid
KW - Membrane
UR - http://www.scopus.com/inward/record.url?scp=84892174478&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892174478&partnerID=8YFLogxK
U2 - 10.1042/BJ20130960
DO - 10.1042/BJ20130960
M3 - Article
C2 - 24215562
AN - SCOPUS:84892174478
VL - 457
SP - 463
EP - 472
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 3
ER -