Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 13, Pages 3391-3395Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201713167
Keywords
biophysics; hemeproteins; lipids; membranes; nanodiscs
Categories
Funding
- NIH [GM084018]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM084018] Funding Source: NIH RePORTER
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Although membrane environment is known to boost drug metabolism by mammalian cytochromeP450s, the factors that stabilize the structural folding and enhance protein function are unclear. In this study, we use peptide-based lipid nanodiscs to trap the lipid boundaries of microsomal cytochromeP450 2B4. We report the first evidence that CYP2B4 is able to induce the formation of raft domains in a biomimetic compound of the endoplasmic reticulum. NMR experiments were used to identify and quantitatively determine the lipids present in nanodiscs. A combination of biophysical experiments and molecular dynamics simulations revealed a sphingomyelin binding region in CYP2B4. The protein-induced lipid raft formation increased the thermal stability of P450 and dramatically altered ligand binding kinetics of the hydrophilic ligand BHT. These results unveil membrane/protein dynamics that contribute to the delicate mechanism of redox catalysis in lipid membrane.
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