title: An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A.
abstract: The enzyme carnitine palmitoyltransferase 1 (CPT1), which is anchored in the outer mitochondrial membrane (OMM), controls the rate-limiting step in fatty acid β-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 Nα and Nβ, that interchange in a switch-like manner in response to offered binding surface curvature. Structure-based site-directed mutageneses of native CPT1A suggest Nα to be inhibitory and Nβ to be noninhibitory, with the relative Nα/Nβ 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 Nα-OMM associations that alter the Nα/Nβ ratio. For enzymes residing at the membrane-water interface, this constitutes an integrative regulatory mechanism of exceptional sophistication.
authors: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
authors: Jampani N
authors: JN
authors: Rao
authors: Metabolic and Vascular Health Division, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors: Gemma Z L
authors: GZL
authors: Warren
authors: Metabolic and Vascular Health Division, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors: Sara
authors: S
authors: Estolt-Povedano
authors: Metabolic and Vascular Health Division, Warwick Medical School, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, United Kingdom.
authors: Victor A
authors: VA
authors: Zammit
authors: Department of Biochemistry and Molecular Biology and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. Electronic address: tulmer@usc.edu.
authors: Tobias S
authors: TS
authors: Ulmer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008823:Micelles; D008928:Mitochondria / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010100:Oxygen / Q000737:chemistry; D017434:Protein Structure, Tertiary; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D005227:Fatty Acids; D008823:Micelles; D002334:Carnitine O-Palmitoyltransferase; D010100:Oxygen