Structural characterization of the regulatory domain of brain carnitine palmitoyltransferase 1.

ABSTRACT: Neurons contain a mammalian-specific isoform of the enzyme carnitine palmitoyltransferase 1 (CPT1C) that couples malonyl-CoA to ceramide levels thereby contributing to systemic energy homeostasis and feeding behavior. In contrast to CPT1A, which controls the rate-limiting step of long-chain fatty acid ?-oxidation in all tissues, the biochemical context and regulatory mechanism of CPT1C are unknown. CPT1 enzymes are comprised of an N-terminal regulatory domain and a C-terminal catalytic domain (CD) that are separated by two transmembrane helices. In CPT1A, the regulatory domain, termed N, adopts an inhibitory and non-inhibitory state, N? and N?, respectively, which differ in their association with the CD. To provide insight into the regulatory mechanism of CPT1C, we have determined the structure of its regulatory domain (residues Met1-Phe50) by NMR spectroscopy. In relation to CPT1A, the inhibitory N? state was found to be structurally homologues whereas the non-inhibitory N? state was severely destabilized, suggesting a change in overall regulation. The destabilization of N? may contribute to the low catalytic activity of CPT1C relative to CPT1A and makes its association with the CD unlikely. In analogy to the stabilization of N? by the CPT1A CD, non-inhibitory interactions of N of CPT1C with another protein may exist.

SUBMITTER: Samanta S 

PROVIDER: S-EPMC3907070 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature