Structure and Mechanism of F
            <sub>0</sub>
            F
            <sub>1</sub>
            ‐Type ATP Synthases and ATPases

Penefsky, Harvey S.; Cross, Richard L.

doi:10.1002/9780470123102.ch4

Cited by 96 publications

(9 citation statements)

References 145 publications

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“…The first ATP binds with very high affinity, K D =0.001 nM for mitochondrial enzyme and 0.2 nM for E. coli F 1 , and is hydrolyzed, but the products, ADP and Pi, are released very slowly [29,44]. Consistent with the 18 O experiments, the ratio of the hydrolysis and synthesis rate constants is found to be close to unity [45,46].…”

Section: Partial Reaction and Rotation Steps In Steady Statesupporting

confidence: 63%

“…The three sites primarily in the β subunits carry out ATP synthesis and hydrolysis and, as will be discussed below, all three participate in steady state rotational catalysis. The sites primarily in the α subunits are non-catalytic and exchange bound nucleotide very slowly (see [28][29][30] for reviews). The terminal regions of the γ subunit form a long coiledcoil, which penetrates into the core of the α/β pseudo-hexamer (Fig.…”

Section: Rotation In the Catalytic Mechanismmentioning

confidence: 99%

“…Studies of the catalytic mechanism have been extensively covered in many excellent reviews (see [9,29,[32][33][34]). Here, we will only discuss the more recent experiments which have brought us to our current understanding of the three site, rotational catalytic mechanism.…”

Section: Rotation In the Catalytic Mechanismmentioning

confidence: 99%

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The rotary mechanism of the ATP synthase

Nakamoto

Scanlon

Al‐Shawi

2008

Archives of Biochemistry and Biophysics

167

126

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The F O F 1 ATP synthase is a large complex of at least 22 subunits, more than half of which are in the membranous F O sector. This nearly ubiquitous transporter is responsible for the majority of ATP synthesis in oxidative and photo-phosphorylation, and its overall structure and mechanism have remained conserved throughout evolution. Most examples utilize the proton motive force to drive ATP synthesis except for a few bacteria, which use a sodium motive force. A remarkable feature of the complex is the rotary movement of an assembly of subunits that plays essential roles in both transport and catalytic mechanisms. This review addresses the role of rotation in catalysis of ATP synthesis/hydrolysis and the transport of protons or sodium. KeywordsATP synthase; kinetic mechanism; rotation; transport Like many transporters, the F O F 1 ATP synthase (or F-type ATPase) has been a fascinating subject for the study of a complex membrane-associated process. The ATP synthase is a critically important activity that carries out synthesis of ATP from ADP and Pi driven by a proton motive force, Δµ H+ , or sodium motive force, Δµ Na+ . This final step of oxidative or photo-phosphorylation provides the vast majority of ATP in the cell. The proton or sodium motive force is also needed to power other membrane processes such as secondary transporters or in the case of bacteria, flagellum rotation. In anaerobic conditions, facultative bacteria use the ATP synthase as an ATP-driven H + or Na + pump to generate the Δµ H+ , or Δµ Na+ (see [1] for a textbook review.) The F O F 1 complex is nearly ubiquitous in the cell membranes of eubacteria, in the thylakoid membrane of chloroplasts, and the inner membrane of mitochondria. The transporter has remained structurally and mechanistically conserved, except for a few additional domains or subunits in mitochondria, which may play roles in regulation or assembly.Many years of innovative biochemical, genetic, kinetic, and thermodynamic studies led to the first structural solution of the catalytic F 1 portion of the complex by Walker, Leslie and coworkers [2] in 1994. This landmark structure provided critical information on the catalytic portion of the complex but the subunit arrangement of much of the rest of the complex was still not elucidated. The partial F 1 structure, which at the time was the largest asymmetric unit solved, provided the impetus and the structural information needed to test the notion that the

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Section: Partial Reaction and Rotation Steps In Steady Statesupporting

confidence: 63%

Section: Rotation In the Catalytic Mechanismmentioning

confidence: 99%

See 1 more Smart Citation

The rotary mechanism of the ATP synthase

Nakamoto

Scanlon

Al‐Shawi

2008

Archives of Biochemistry and Biophysics

167

126

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“…F 1 contains multiple subunits (␣ 3 ␤ 3 ␥, ␦, ⑀) and is bound on the membrane by its interaction with F 0 . F 0 functions as a proton pump, and F1 uses the energy produced from proton translocation to synthesize ATP (Penefsky and Cross, 1991). The ATP synthase localizes primarily to inner mitochondria membrane (Boyer, 1997).…”

Section: Discussionmentioning

confidence: 99%

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

Barr

2005

MBoC

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Caenorhabditis elegans is a powerful model to study the molecular basis of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is caused by mutations in the polycystic kidney disease (PKD)1 or PKD2 gene, encoding polycystin (PC)-1 or PC-2, respectively. The C. elegans polycystins LOV-1 and PKD-2 are required for male mating behaviors and are localized to sensory cilia. The function of the evolutionarily conserved polycystin/lipoxygenase/␣-toxin (PLAT) domain found in all PC-1 family members remains an enigma. Here, we report that ATP-2, the ␤ subunit of the ATP synthase, physically associates with the LOV-1 PLAT domain and that this interaction is evolutionarily conserved. In addition to the expected mitochondria localization, ATP-2 and other ATP synthase components colocalize with LOV-1 and PKD-2 in cilia. Disrupting the function of the ATP synthase or overexpression of atp-2 results in a male mating behavior defect. We further show that atp-2, lov-1, and pkd-2 act in the same molecular pathway. We propose that the ciliary localized ATP synthase may play a previously unsuspected role in polycystin signaling. INTRODUCTIONAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting one per 400-1000 individuals (Igarashi and Somlo, 2002). This syndrome is characterized by progressive development of fluid-filled, epithelial cysts in the kidney, liver, and pancreas and accounts for ϳ10% of all cases of endstage renal disease. Mutation in either the polycystic kidney disease (PKD)1 or PKD2 gene accounts for 95% of all ADPKD cases. PKD1 encodes polycystin (PC)-1, a 4302-amino acid protein with a large extracellular domain, a G protein-coupled receptor proteolytic site (GPS), 11 predicted transmembrane (TM) domains, and an intracellular C terminus. The polycystin/lipoxygenase/␣-toxin (PLAT) domain is located in the first cytoplasmic loop between TM1 and TM2 and has been postulated to be involved in membrane-protein or protein-protein interactions (Bateman and Sandford, 1999). This domain is conserved in all PC-1 family members and also found in a variety of membrane-or lipid-associated proteins. Polycystin-2 (PC-2, encoded by PKD2) shares homology with the transient receptor protein (TRP) channels and acts as a nonselective cation channel. Defects in PC-1 or PC-2 signaling may result in epithelial dedifferentiation and cyst formation. Several signaling pathways regulated by PC-1 and PC-2 have been identified using in vitro approaches, including G protein signaling, JAK/STAT cell cycle regulation, and mechanotransduction (Boletta and Germino, 2003), but the physiological relevance to normal and disease states remains unclear.The nematode C. elegans is a simple but powerful animal model for studying basic molecular mechanisms underlying human ADPKD. The C. elegans LOV-1 and PKD-2 proteins are homologues of human PC-1 and PC-2 (Barr and Sternberg, 1999;Barr et al., 2001). lov-1 (location of vulva) and pkd-2 act nonredundantly in the same genetic pathway and are requi...

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“…Once bound, this nucleotide undergoes oxygen exchange with medium water (a process called unisite catalysis) as the nucleotide undergoes rapid cycles of hydrolysis and resynthesis. Release of ADP is very slow (4,5).…”

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confidence: 99%

The Escherichia coli F1F0 ATP Synthase Displays Biphasic Synthesis Kinetics

Tomashek

Glagoleva

Brusilow

2004

Journal of Biological Chemistry

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The F 1 F 0 proton-translocating ATPase/synthase is the primary generator of ATP in most organisms growing aerobically. Kinetic assays of ATP synthesis have been conducted using enzymes from mitochondria and chloroplasts. However, limited data on ATP synthesis by the model Escherichia coli enzyme are available, mostly because of the lack of an efficient and reproducible assay. We have developed an optimized assay and have collected synthase kinetic data over a substrate concentration range of 2 orders of magnitude for both ADP and P i from the synthase enzyme of E. coli. Negative and positive cooperativity of substrate binding and positive catalytic cooperativity were all observed. ATP synthesis displayed biphasic kinetics for ADP indicating that 1) the enzyme is capable of catalyzing efficient ATP synthesis when only two of three catalytic sites are occupied by ADP; and 2) occupation of the third site further activates the rate of catalysis.The F-type proton-translocating ATPase/synthases are a family of enzymes primarily responsible for the oxidative phosphorylation of ADP to form ATP (1-3). These membrane-bound enzymes are found in the inner membranes of mitochondria, the thylakoid membranes of chloroplasts, and the inner membranes of bacteria. The synthase uses energy from an electrochemical gradient of protons generated by a membrane-bound electron transport chain to drive the binding and catalysis of ADP and P i and the release of ATP. The actual synthesis (or hydrolysis in the reverse direction) reaction of the triphosphate nucleotide occurs in one of three catalytic sites under tightly bound conditions (the "tight" site or site 1) with a K eq ϳ 1; thus, the energy provided by the proton gradient is used primarily to alter the binding of the substrates and products, and hence the "binding change" mechanism.Certain aspects of the enzymes are generally accepted. In the direction of hydrolysis, given an enzyme with three empty catalytic sites, MgATP binds to the first site with very high affinity (nanomolar range). Once bound, this nucleotide undergoes oxygen exchange with medium water (a process called unisite catalysis) as the nucleotide undergoes rapid cycles of hydrolysis and resynthesis. Release of ADP is very slow (4, 5).As the concentration of ATP is increased and approaches the K d values for the remaining two sites, the rate of product release increases, a phenomenon called catalytic cooperativity (6). The affinity of the second site for MgATP (micromolar range) is lower than the first, and the affinity of the third site is lower still (range, 10 -100 M). Thus, the binding of nucleotide exhibits negative cooperativity.There has been controversy recently regarding the necessity of substrate binding to subsequent sites for the activation of rapid catalysis. On one hand, it has been argued and demonstrated that some enzymes, particularly those from mitochondria and chloroplasts, display bisite activation, i.e. the binding of substrate(s) at the second site is necessary and sufficient to accelerate the ...

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Structure and Mechanism of F ₀ F ₁ ‐Type ATP Synthases and ATPases

Cited by 96 publications

References 145 publications

The rotary mechanism of the ATP synthase

The rotary mechanism of the ATP synthase

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

The Escherichia coli F1F0 ATP Synthase Displays Biphasic Synthesis Kinetics

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Structure and Mechanism of F 0 F 1 ‐Type ATP Synthases and ATPases

Cited by 96 publications

References 145 publications

The rotary mechanism of the ATP synthase

The rotary mechanism of the ATP synthase

ATP-2 Interacts with the PLAT Domain of LOV-1 and Is Involved inCaenorhabditis elegansPolycystin Signaling

The Escherichia coli F1F0 ATP Synthase Displays Biphasic Synthesis Kinetics

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Structure and Mechanism of F ₀ F ₁ ‐Type ATP Synthases and ATPases