Picturing the Membrane-assisted Choreography of Cytochrome P450 with Lipid Nanodiscs

Abstract

Cytochrome P450, a family of monooxygenase enzymes, is organized as a catalytic metabolon, and requires enzymatic partners as well as environmental factors that tune its complex dynamic activity. P450 and its reducing counterparts are membrane-bound proteins which are believed to dynamically interact to form functional complexes. Increasing experimental evidence signifies the role (s) of protein-lipid interactions in P450's catalytic function and efficiency. The challenges posed by the membrane have severely limited high-resolution understanding of the molecular interfaces of these interactions. Nevertheless, recent NMR studies have provided piercing insights into the dynamic structural interactions that enable the function of P450. In this review, we will discuss different biomimetic approaches relevant to unveil molecular interplays at the membrane, focusing on our recent work on lipid-nanodiscs. We also highlight the need to expand the use of nanodiscs, and the power of a combination of cutting-edge solution and solid-state NMR techniques, to study the dynamic structures of P450 as well as other membrane-proteins.

Keywords: cytochrome P450; endoplasmic reticulum; lipid exchange; membrane rafts; nanodiscs.