Role of membrane curvature on the activation/deactivation of Carnitine Palmitoyltransferase 1A: A coarse grain molecular dynamic study

Abstract

Carnitine Palmitoyltransferase 1A (CPT 1A) is an enzyme anchored to the outer mitochondrial membrane (OMM), where it regulates the passage of fatty acids into the mitochondria and intervenes in the process of β-oxidation of long-chain fatty acids. Although CPT 1A is inhibited by malonyl-CoA, its activity is also modulated by the curvature of OMM. This modulation depends on the behavior of the N-terminal domain (NTD), which can be adsorbed onto the OMM (nonactive CPT 1A) or interacting with the C-terminal domain (active CPT 1A). Aimed to provide mechanistic insights on the regulatory mechanism of CPT 1A, we studied the influence of the bilayer curvature on the NTD behavior through a series of coarse-grained (CG) molecular dynamics simulations using curved and planar membranes. Comparative analysis suggests that the main determinant for the activation/deactivation of the enzyme is the tilt angle orientation of the transmembrane (TM) domains. Planar membranes induce a wide variation on the tilt angle orientation of TM helices, while curved geometries promote small angles with the membrane normal. Our results identify the first TM domain as an important component of the membrane sensing mechanism.