The structure of the membrane extrinsic region of bovine ATP synthase

Rees, David M.; Leslie, Andrew G. W.; Walker, John E.

doi:10.1073/pnas.0910365106

Cited by 164 publications

(205 citation statements)

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“…To more precisely define the specific partner(s) of CyPD within this complex, we devised conditions optimizing its binding to the ATP synthase, while separating the subunits of the peripheral stalk. The first condition was met by using 10 mM Pi and low ionic strength (24); the second condition was met by adding a low concentration of SDS to the Triton X-100-based extraction buffer and using a polyclonal antibody against a peptide mapping near the C terminus of OSCP, which disrupts the interaction of the OSCP C-terminal domain with the N-terminal portion of subunit b (25). This strategy allowed the immunoprecipitation of individual OSCP, b, and d subunits, because no other stalk protein was detected in the specific immunoblots (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The molecular structures of the membrane extrinsic region of the bovine ATP synthase (Protein Data Bank ID code 2WSS, chains) (25) and human CyPD complexed with CsA (Protein Data Bank ID code 2Z6W) (52) were used for the calculation of surface potential with the Generalized Born model (53) and isopotential surfaces within the PoissonBoltzmann theoretical framework (54). The calculations performed on the apoform of CyPD and OSCP in the ATP-synthase complex did not reveal apparent complementarity in the surface potential and isopotential curves because of the complexity and extension of OSCP in the context of ATP synthase.…”

Section: Methodsmentioning

confidence: 99%

“…This complex is formed by the catalytic F 1 , the membrane-bound proton-translocating F O , and a lateral stalk linking F 1 and F O . CyPD binds the lateral stalk, which acts as a stator to counter the tendency of the α 3 β 3 -subcomplex of the F 1 -catalytic domain to rotate with the rotor containing the F 1 subunits-γ, -δ, and -e and a ring of F O subunits c (25). CyPD binding requires Pi and results in partial inhibition of ATP synthase activity, whereas CsA displaces CyPD, resulting in enzyme reactivation (24).…”

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confidence: 99%

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Dimers of mitochondrial ATP synthase form the permeability transition pore

Giorgio

Stockum

Antoniel³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

835

882

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Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalk of the F O F 1 ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca 2+ like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca 2+ . Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca 2+ , addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg 2+ /ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Dimers of mitochondrial ATP synthase form the permeability transition pore

Giorgio

Stockum

Antoniel³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

835

882

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“…2). Alternatively, the X-ray structure of the bovine F 1 ∕peripheral stalk assembly [2WSS; (15)] was placed into the subtomogram average (Fig. S3).…”

Section: Resultsmentioning

confidence: 99%

“…10). The atomic structures for both the yeast and bovine F 1 ∕rotor ring assemblies (11)(12)(13) have been determined by X-ray crystallography, as has part of the bovine peripheral stalk subcomplex (14,15).…”

mentioning

confidence: 99%

Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Davies

Anselmi

Wittig

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

440

510

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We used electron cryotomography of mitochondrial membranes from wild-type and mutant Saccharomyces cerevisiae to investigate the structure and organization of ATP synthase dimers in situ. Subtomogram averaging of the dimers to 3.7 nm resolution revealed a V-shaped structure of twofold symmetry, with an angle of 86°between monomers. The central and peripheral stalks are well resolved. The monomers interact within the membrane at the base of the peripheral stalks. In wild-type mitochondria ATP synthase dimers are found in rows along the highly curved cristae ridges, and appear to be crucial for membrane morphology. Strains deficient in the dimer-specific subunits e and g or the first transmembrane helix of subunit 4 lack both dimers and lamellar cristae. Instead, cristae are either absent or balloon-shaped, with ATP synthase monomers distributed randomly in the membrane. Computer simulations indicate that isolated dimers induce a plastic deformation in the lipid bilayer, which is partially relieved by their side-by-side association. We propose that the assembly of ATP synthase dimer rows is driven by the reduction in the membrane elastic energy, rather than by direct protein contacts, and that the dimer rows enable the formation of highly curved ridges in mitochondrial cristae.membrane-protein oligomerization | membrane deformation | molecular dynamics simulations | bioenergetics | ATP synthesis T he F 1 F o ATP synthase is a highly conserved molecular machine that catalyses the production of ATP from ADP and P i in energy-converting membranes of eukaryotes and bacteria.

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Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase

et al. 2020

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Enzyme subunit interfaces have remarkable potential in drug design as both target and scaffold for their own inhibitors. We show an evolution‐driven strategy for the de novo design of peptide inhibitors targeting interfaces of the Escherichia coli FoF1‐ATP synthase as a case study. The evolutionary algorithm ROSE was applied to generate diversity‐oriented peptide libraries by engineering peptide fragments from ATP synthase interfaces. The resulting peptides were scored with PPI‐Detect, a sequence‐based predictor of protein–protein interactions. Two selected peptides were confirmed by in vitro inhibition and binding tests. The proposed methodology can be widely applied to design peptides targeting relevant interfaces of enzymatic complexes.

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The structure of the membrane extrinsic region of bovine ATP synthase

Cited by 164 publications

References 29 publications

Dimers of mitochondrial ATP synthase form the permeability transition pore

Dimers of mitochondrial ATP synthase form the permeability transition pore

Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase

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The structure of the membrane extrinsic region of bovine ATP synthase

Cited by 164 publications

References 29 publications

Dimers of mitochondrial ATP synthase form the permeability transition pore

Dimers of mitochondrial ATP synthase form the permeability transition pore

Structure of the yeast F 1 F o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for FOF1‐ATP synthase

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Product

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Structure of the yeast F ₁ F _o -ATP synthase dimer and its role in shaping the mitochondrial cristae

Engineering protein fragments via evolutionary and protein–protein interaction algorithms: de novo design of peptide inhibitors for F_OF₁‐ATP synthase