Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 39, Pages 10860-10865Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1612035113
Keywords
Caldalkalibacillus thermarum; F-1-ATPase; structure; inhibition; regulation
Categories
Funding
- Medical Research Council UK [MC_U1065663150, MC_U105184325, MR/M009858/1]
- James Cook Fellowship from the Royal Society of New Zealand
- Health Research Council of New Zealand
- MRC [MC_U105184325, MC_EX_MR/M009858/1] Funding Source: UKRI
- Medical Research Council [MC_EX_MR/M009858/1, MC_U105184325] Funding Source: researchfish
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The crystal structure has been determined of the F-1-catalytic domain of the F-ATPase from Caldalkalibacillus thermarum, which hydrolyzes adenosine triphosphate (ATP) poorly. It is very similar to those of active mitochondrial and bacterial F-1-ATPases. In the F-ATPase from Geobacillus stearothermophilus, conformational changes in the e-subunit are influenced by intracellular ATP concentration and membrane potential. When ATP is plentiful, the epsilon-subunit assumes a down state, with an ATP molecule bound to its two C-terminal alpha-helices; when ATP is scarce, the alpha-helices are proposed to inhibit ATP hydrolysis by assuming an up state, where the alpha-helices, devoid of ATP, enter the alpha(3)beta(3)-catalytic region. However, in the Escherichia coli enzyme, there is no evidence that such ATP binding to the epsilon-subunit is mechanistically important for modulating the enzyme's hydrolytic activity. In the structure of the F-1-ATPase from C. thermarum, ATP and a magnesium ion are bound to the alpha-helices in the down state. In a form with a mutated epsilon-subunit unable to bind ATP, the enzyme remains inactive and the epsilon-subunit is down. Therefore, neither the gamma-subunit nor the regulatory ATP bound to the epsilon-subunit is involved in the inhibitory mechanism of this particular enzyme. The structure of the alpha(3)beta(3)-catalytic domain is likewise closely similar to those of active F-1-ATPases. However, although the beta(E)-catalytic site is in the usual open conformation, it is occupied by the unique combination of an ADP molecule with no magnesiumion and a phosphate ion. These bound hydrolytic products are likely to be the basis of inhibition of ATP hydrolysis.
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