An Environment-dependent Structural Switch Underlies the Regulation of Carnitine Palmitoyltransferase 1A

作者：Rao Jampani N; Warren Gemma Z L; Estolt Povedano Sara; Zammit Victor A; Ulmer Tobias S^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286(49): 42545-42554.

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 N alpha and N beta, that interchange in a switch-like manner in response to offered binding surface curvature. Structure-based site-directed mutageneses of native CPT1A suggest N alpha to be inhibitory and N beta to be noninhibitory, with the relative N alpha/N beta 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 N alpha-OMM associations that alter the N alpha/N beta ratio. For enzymes residing at the membrane-water interface, this constitutes an integrative regulatory mechanism of exceptional sophistication.

• 出版日期2011-12-9