Chemomechanical coupling of human mitochondrial F1-ATPase motor

Suzuki, Toshiharu; Tanaka, Kazumi; Wakabayashi, Chiaki; Saita, Ei-ichiro; Yoshida, Masasuke

doi:10.1038/nchembio.1635

Cited by 93 publications

(169 citation statements)

References 47 publications

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“…The presence of dwells is suggested from the angle histogram of rotation that awaits extensive analysis. As expected from high sequence conservation between bovine F 1 and human F 1 , these motor characteristics of bovine F 1 are similar to those of human F 1 ( k on , 2.7 ± 0.3 × 10 7 m −1 ·s −1 ; rotation speed, 705 ± 75 rps) 5.…”

Section: Resultssupporting

confidence: 69%

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Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

et al. 2016

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F 1 ‐ ATP ase (F 1 ) is a multisubunit water‐soluble domain of F o F 1‐ ATP synthase and is a rotary enzyme by itself. Earlier genetic studies using yeast suggested that two factors, Atp11p and Atp12p, contribute to F 1 assembly. Here, we show that their mammalian counterparts, AF 1 and AF 2, are essential and sufficient for efficient production of recombinant bovine mitochondrial F 1 in Escherichia coli cells. Intactness of the function and conformation of the E. coli ‐expressed bovine F 1 was verified by rotation analysis and crystallization. This expression system opens a way for the previously unattempted mutation study of mammalian mitochondrial F 1 .

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Section: Resultssupporting

confidence: 69%

“…5. Two cysteine residues were introduced into a globular domain of γ‐subunit (γAla99Cys and γSer191Cys).…”

Section: Methodsmentioning

confidence: 99%

Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

et al. 2016

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“…This result suggests a possible third substep, yet unresolved, for the E. coli F 1 (34,35). This third step could be associated with phosphate release (31,36). Alternatively, the bacterial γ-subunit or its interface with the c ring could be softer, especially for the thermophilic Bacillus PS3 F 1 , in which only two substeps have been found after extensive single-molecule experiments.…”

Section: Significancementioning

confidence: 92%

“…D 2 is thus ∼10 times smaller than the hydrodynamic limit, which is reasonable because the protruded part is slowed down by interactions, mainly salt bridges, with the tips of the αβ-subunits. (31), with the cost of ATP spread proportionally among them. The free energy of the system for the discrete (sub) steps then becomes…”

Section: Significancementioning

confidence: 99%

“…The model quantifies the magnitude of transient elastic energy storage compensating for the incommensurate rotational symmetries of the F o and F 1 motors (30). The resulting energetic constraints allow us to map out a detailed pathway for their coupled rotary motions, and to rationalize the finer stepping of the mammalian F 1 motor seen in recent experiments (31), with only eight c subunits in the corresponding F o motor. By quantifying the frictional dissipation, we identify a key contributor to the high thermodynamic efficiency of the F 1 motor.…”

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confidence: 99%

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Elasticity, friction, and pathway of γ-subunit rotation in F _o F ₁ -ATP synthase

Okazaki

Hummer

2015

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

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We combine molecular simulations and mechanical modeling to explore the mechanism of energy conversion in the coupled rotary motors of F o F 1 -ATP synthase. A torsional viscoelastic model with frictional dissipation quantitatively reproduces the dynamics and energetics seen in atomistic molecular dynamics simulations of torquedriven γ-subunit rotation in the F 1 -ATPase rotary motor. The torsional elastic coefficients determined from the simulations agree with results from independent single-molecule experiments probing different segments of the γ-subunit, which resolves a long-lasting controversy. At steady rotational speeds of ∼1 kHz corresponding to experimental turnover, the calculated frictional dissipation of less than k B T per rotation is consistent with the high thermodynamic efficiency of the fully reversible motor. Without load, the maximum rotational speed during transitions between dwells is reached at ∼1 MHz. Energetic constraints dictate a unique pathway for the coupled rotations of the F o and F 1 rotary motors in ATP synthase, and explain the need for the finer stepping of the F 1 motor in the mammalian system, as seen in recent experiments. Compensating for incommensurate eightfold and threefold rotational symmetries in F o and F 1 , respectively, a significant fraction of the external mechanical work is transiently stored as elastic energy in the γ-subunit. The general framework developed here should be applicable to other molecular machines.bioenergetics | molecular motor | mechanochemical coupling F o F 1 -ATP synthase is essential for life. From bacteria to human, this protein synthesizes ATP from ADP and inorganic phosphate P i in its F 1 domain, powered by an electrochemical proton gradient that drives the rotation of its membrane-embedded F o domain (1-5). Its two rotary motors, F 1 and F o , are coupled through the γ-subunit forming their central shaft (2). ATP synthase is a fully reversible motor, in which the rotational direction switches according to different sources of energy (2, 6). In hydrolysis mode, the F 1 motor pumps protons against an electrochemical gradient across the membrane-embedded F o part, converting ATP to ADP and P i (7,8).F 1 has a symmetric ring structure composed of three αβ-subunits with the asymmetric γ-subunit sitting inside the ring (9, 10). Each αβ-subunit has a catalytic site located at the αβ-domain interface. The F 1 ring has a pseudothreefold symmetry with the three αβ-subunits taking three different conformations, E (empty), TP (ATP-bound), and DP (ADP bound) (9-11). The F o part is composed of a c ring and an a subunit (3, 12). Driven by protons passing through the interface of the c ring and the a subunit, the c ring rotates together with the γ-subunit (rotor) relative to the a subunit, which is connected to the F 1 ring through the peripheral stalk of the b subunit (stator) (12). Interestingly, in nature, one finds a large variation in the number of subunits in the c ring. In animal mitochondria, one finds c 8 rings, requiring a minimal number of e...

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H+‐slip correlated to rotor free‐wheeling as cause of F₁F_O‐ATPase dysfunction in primary mitochondrial disorders

Nesci,

Romeo

2024

Medicinal Research Reviews

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Inborn errors of metabolism are related to mitochondrial disorders caused by dysfunction of the oxidative phosphorylation (OXPHOS) system. Congenital hypermetabolism in the infant is a rare disease belonging to Luft syndrome, nonthyroidal hypermetabolism, arising from a singular example of a defect in OXPHOS. The mitochondria lose coupling of mitochondrial substrates oxidation from the ADP phosphorylation. Since Luft syndrome is due to uncoupled cell respiration responsible for deficient in ATP production that originates in the respiratory complexes, a de novo heterozygous variant in the catalytic subunit of mitochondrial F1FO‐ATPase arises as the main cause of an autosomal dominant syndrome of hypermetabolism associated with dysfunction in ATP production, which does not involve the respiratory complexes. The F1FO‐ATPase works as an embedded molecular machine with a rotary action using two different motor engines. The FO, which is an integral domain in the membrane, dissipates the chemical potential difference for H+, a proton motive force (Δp), across the inner membrane to generate a torsion. The F1 domain—the hydrophilic portion responsible for ATP turnover—is powered by the molecular rotary action to synthesize ATP. The structural and functional coupling of F1 and FO domains support the energy transduction for ATP synthesis. The dissipation of Δp by means of an H+ slip correlated to rotor free‐wheeling of the F1FO‐ATPase has been discovered to cause enzyme dysfunction in primary mitochondrial disorders. In this insight, we try to offer commentary and analysis of the molecular mechanism in these impaired mitochondria.

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Chemomechanical coupling of human mitochondrial F1-ATPase motor

Cited by 93 publications

References 47 publications

Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Elasticity, friction, and pathway of γ-subunit rotation in F _o F ₁ -ATP synthase

H+‐slip correlated to rotor free‐wheeling as cause of F₁F_O‐ATPase dysfunction in primary mitochondrial disorders

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Chemomechanical coupling of human mitochondrial F1-ATPase motor

Cited by 93 publications

References 47 publications

Expression of mammalian mitochondrial F1‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Expression of mammalian mitochondrial F1‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Elasticity, friction, and pathway of γ-subunit rotation in F o F 1 -ATP synthase

H+‐slip correlated to rotor free‐wheeling as cause of F1FO‐ATPase dysfunction in primary mitochondrial disorders

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Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Expression of mammalian mitochondrial F₁‐ATPase in Escherichia coli depends on two chaperone factors, AF1 and AF2

Elasticity, friction, and pathway of γ-subunit rotation in F _o F ₁ -ATP synthase

H+‐slip correlated to rotor free‐wheeling as cause of F₁F_O‐ATPase dysfunction in primary mitochondrial disorders