Ligand-Induced Conformational Changes within a Hexameric Acyl-CoA Thioesterase

M Marfori, B. Kobe, Jade Forwood

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)
28 Downloads (Pure)

Abstract

Acyl-coenzyme A (acyl-CoA) thioesterases play a crucial role in the metabolism of activated fatty acids, coenzyme A, and other metabolic precursor molecules including arachidonic acid and palmitic acid. These enzymes hydrolyze coenzyme A from acyl-CoA esters to mediate a range of cellular functions including -oxidation, lipid biosynthesis, and signal transduction. Here, we present the crystal structure of a hexameric hot-dog domain-containing acyl-CoA thioesterase from Bacillus halodurans in the apo-form and provide structural and comparative analyses to the coenzyme A-bound form to identify key conformational changes induced upon ligand binding. We observed dramatic ligand-induced changes at both the hot-dog dimer and the trimer-of-dimer interfaces; the dimer interfaces in the apostructure differ by over 20% and decrease to about half the size in the ligand-bound state. We also assessed the specificity of the enzyme against a range of fatty acyl-CoA substrates and have identified a preference for short-chain fatty acyl-CoAs. Coenzyme A was shown both to negatively regulate enzyme activity, representing a direct inhibitory feedback, and consistent with the structural data, to destabilize the quaternary structure of the enzyme. Coenzyme A-induced conformational changes in the C-terminal helices of enzyme were assessed through mutational analysis and shown to play a role in regulating enzyme activity. The conformational changes are likely to be conserved from bacteria through to humans and provide a greater understanding, particularly at a structural level, of thioesterase function and regulation.
Original languageEnglish
Pages (from-to)35643-35649
Number of pages7
JournalJournal of Biological Chemistry
Volume286
Issue number41
DOIs
Publication statusPublished - Oct 2011

Fingerprint

Dive into the research topics of 'Ligand-Induced Conformational Changes within a Hexameric Acyl-CoA Thioesterase'. Together they form a unique fingerprint.

Cite this