An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A

J Biol Chem. 2011 Dec 9;286(49):42545-42554. doi: 10.1074/jbc.M111.306951. Epub 2011 Oct 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Carnitine O-Palmitoyltransferase / chemistry*
  • Dose-Response Relationship, Drug
  • Fatty Acids / chemistry
  • Fatty Acids / metabolism
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Magnetic Resonance Spectroscopy / methods
  • Mice
  • Micelles
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • Molecular Conformation
  • Molecular Sequence Data
  • Oxygen / chemistry
  • Protein Structure, Tertiary
  • Rats
  • Sequence Homology, Amino Acid


  • Fatty Acids
  • Micelles
  • Carnitine O-Palmitoyltransferase
  • Oxygen

Associated data

  • PDB/2LE3