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An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A
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Rao, J. N., Warren, G. Z. L., Estolt-Povedano, S., Zammit, Victor A. and Ulmer, T. S. (2011) An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A. Journal of Biological Chemistry, Vol.286 (No.49). pp. 42545-42554. doi:10.1074/jbc.M111.306951 ISSN 0021-9258.
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Official URL: http://dx.doi.org/10.1074/jbc.M111.306951
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.
| Item Type: | Journal Article | ||||
|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Journal of Biological Chemistry | ||||
| Publisher: | American Society for Biochemistry and Molecular Biology | ||||
| ISSN: | 0021-9258 | ||||
| Official Date: | 2011 | ||||
| Dates: |
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| Volume: | Vol.286 | ||||
| Number: | No.49 | ||||
| Page Range: | pp. 42545-42554 | ||||
| DOI: | 10.1074/jbc.M111.306951 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access |
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