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

Authors: Rao, JN  Warren, GZ  Estolt-Povedano, S  Zammit, VA  Ulmer, TS 
Citation: Rao JN, etal., J Biol Chem. 2011 Dec 9;286(49):42545-54. doi: 10.1074/jbc.M111.306951. Epub 2011 Oct 11.
Pubmed: (View Article at PubMed) PMID:21990363
DOI: Full-text: DOI:10.1074/jbc.M111.306951

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.


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CRRD Object Information
CRRD ID: 8554544
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.