Ligand-induced conformational changes within a hexameric acyl-CoA thioesterase

Marfori, Mary, Kobe, Bostjan and Forwood, Jade K. (2011) Ligand-induced conformational changes within a hexameric acyl-CoA thioesterase. Journal of Biological Chemistry, 286 41: 35643-35649. doi:10.1074/jbc.M111.225953

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Author Marfori, Mary
Kobe, Bostjan
Forwood, Jade K.
Title Ligand-induced conformational changes within a hexameric acyl-CoA thioesterase
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2011-10
Sub-type Article (original research)
DOI 10.1074/jbc.M111.225953
Open Access Status File (Publisher version)
Volume 286
Issue 41
Start page 35643
End page 35649
Total pages 7
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Collection year 2012
Language eng
Formatted 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 β-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 apo-structure 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.
Keyword Rats
Enzyme catalysis
Fatty Acid
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Received for publication, January 27, 2011, and in revised form, June 12, 2011 Published, JBC Papers in Press, August 17, 2011,

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 6 times in Thomson Reuters Web of Science Article | Citations
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