Publication Abstract from PubMed
The enzyme carnitine palmitoyltransferase 1 (CPT1), which is anchored in the outer mitochondrial membrane (OMM), controls the rate-limiting step in fatty acid beta-oxidation in mammalian tissues. It is inhibited by malonyl-CoA, the first intermediate of fatty acid synthesis, and it responds to OMM curvature and lipid characteristics, which reflect long term nutrient/hormone availability. Here, we show that the N-terminal regulatory domain (N) of CPT1A can adopt two complex amphiphilic structural states, termed Nalpha and Nbeta, that interchange in a switch-like manner in response to offered binding surface curvature. Structure-based site-directed mutageneses of native CPT1A suggest Nalpha to be inhibitory and Nbeta to be noninhibitory, with the relative Nalpha/Nbeta ratio setting the prevalent malonyl-CoA sensitivity of the enzyme. Based on the amphiphilic nature of N and molecular modeling, we propose malonyl-CoA sensitivity to be coupled to the properties of the OMM by Nalpha-OMM associations that alter the Nalpha/Nbeta ratio. For enzymes residing at the membrane-water interface, this constitutes an integrative regulatory mechanism of exceptional sophistication.
An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A.,Rao JN, Warren GZ, Estolt-Povedano S, Zammit VA, Ulmer TS J Biol Chem. 2011 Dec 9;286(49):42545-54. Epub 2011 Oct 11. PMID:21990363[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
