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How release of phosphate from mammalian F|1|-ATPase generates a rotary substep.

DOI: 10.1073/pnas.1506465112 DOI Help
PMID: 25918412 PMID Help

Authors: John Bason (MRC Mitochondrial Biology Unit) , Martin Montgomery (MRC Mitochondrial Biology Unit) , Andrew Leslie (MRC Laboratory of Molecular Biology) , John E. Walker (MRC Mitochondrial Biology Unit)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 112 (19) , PAGES 6009 - 6014

State: Published (Approved)
Published: May 2015
Diamond Proposal Number(s): 6641 , 8547

Open Access Open Access

Abstract: The rotation of the central stalk of F1-ATPase is driven by energy derived from the sequential binding of an ATP molecule to its three catalytic sites and the release of the products of hydrolysis. In human F1-ATPase, each 360° rotation consists of three 120° steps composed of substeps of about 65°, 25°, and 30°, with intervening ATP binding, phosphate release, and catalytic dwells, respectively. The F1-ATPase inhibitor protein, IF1, halts the rotary cycle at the catalytic dwell. The human and bovine enzymes are essentially identical, and the structure of bovine F1-ATPase inhibited by IF1 represents the catalytic dwell state. Another structure, described here, of bovine F1-ATPase inhibited by an ATP analog and the phosphate analog, thiophosphate, represents the phosphate binding dwell. Thiophosphate is bound to a site in the Alpha (E) Beta (E)-catalytic interface, whereas in F1-ATPase inhibited with IF1, the equivalent site is changed subtly and the enzyme is incapable of binding thiophosphate. These two structures provide a molecular mechanism of how phosphate release generates a rotary substep as follows. In the active enzyme, phosphate release from the Beta (E)-subunit is accompanied by a rearrangement of the structure of its binding site that prevents released phosphate from rebinding. The associated extrusion of a loop in the beta (E)-subunit disrupts interactions in the Alpha (E) Beta (E)-catalytic interface and opens it to its fullest extent. Other rearrangements disrupt interactions between the Gamma-subunit and the C-terminal domain of the Alpha (E)-subunit. To restore most of these interactions, and to make compensatory new ones, the Gamma-subunit rotates through 25°-30°.

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography

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