![]() (2008) The cytoplasmic loops of subunit a of Escherichia coli ATP synthase may participate in the proton translocating mechanism. Moore, Kyle J Angevine, Christine M Vincent, Owen D et al. Steed, P Ryan Fillingame, Robert H (2009) Aqueous accessibility to the transmembrane regions of subunit c of the Escherichia coli F1F0 ATP synthase. Protein Sci 21:279-88ĭong, Hui Fillingame, Robert H (2010) Chemical reactivities of cysteine substitutions in subunit a of ATP synthase define residues gating H+ transport from each side of the membrane. (2012) Cell-free synthesis of membrane subunits of ATP synthase in phospholipid bicelles: NMR shows subunit a fold similar to the protein in the cell membrane. Uhlemann, Eva-Maria E Pierson, Hannah E Fillingame, Robert H et al. (2013) Interactions between subunits a and b in the rotary ATP synthase as determined by cross-linking. J Biol Chem 288:25535-41ĭeLeon-Rangel, Jessica Ishmukhametov, Robert R Jiang, Warren et al. Moore, Kyle J Fillingame, Robert H (2013) Obstruction of transmembrane helical movements in subunit a blocks proton pumping by F1Fo ATP synthase. Steed, P Ryan Fillingame, Robert H (2014) Residues in the polar loop of subunit c in Escherichia coli ATP synthase function in gating proton transport to the cytoplasm. Steed, P Ryan Kraft, Kaitlin A Fillingame, Robert H (2014) Interacting cytoplasmic loops of subunits a and c of Escherichia coli F1F0 ATP synthase gate H+ transport to the cytoplasm. The principles by which this enzyme works may provide fundamental insights into other transport problems in biology and medicine.įillingame, Robert H Steed, P Ryan (2014) Half channels mediating H(+) transport and the mechanism of gating in the Fo sector of Escherichia coli F1Fo ATP synthase. Closely related enzymes are responsible for vesicular acidification in human cells, and work by a similar rotary mechanism. Abnormalities in the enzyme lead to human disease. The ATP synthase is central to cellular function-it makes the ATP. Ultimately, we hope to define an atomic resolution structure that can be used in mechanistic studies. ![]() Initially, the global fold of the purified protein in solution will be compared to that in the membrane using spin-labeled protein to establish appropriate solution conditions. Simultaneously, we will attempt to determine the solution structure of purified subunit a by NMR. Aqueous access pathways in subunit a mediating H+ transport from membrane surfaces to the H+ binding site in subunit c will be defined, and the mechanism of gating H+ access to the two sides of the membrane probed. The global fold and packing of subunit a in native Escherichia coli membranes will be determined by cross link analysis. This proposal focuses on the structure of subunit a, with the ultimate goal of defining its role in coupling H+ transport to c-ring rotation. The concerted rotation of helices at the subunit a-c interface is proposed to mechanically drive the stepwise movement of the c-ring. Biochemical evidence indicates that one of the helices of subunit c, which resides at the interface with subunit a, rotates between two different conformations. The structure of subunit c was solved by solution NMR and the c-ring has been modeled. The mechanism of coupling H+ transport and c-ring rotation is poorly understood. A stator complex of F0 subunits a and b and F1 subunit delta extends from the membrane to the top of the F1 molecule and holds alpha-3-beta-3 fixed, relative to the membrane, allowing the c-gamma complex to rotate within. H+ transport through transmembrane F0 drives rotation of an oligomeric ring of c subunits connected with gamma, and results in ATP synthesis in catalytic sites at the alpha-beta interface. Rotation of subunit gamma within the core of the alpha-3-beta-3 hexamer of F1 drives ATP synthesis by a unique rotary catalytic mechanism. The H+-transporting F1F0 ATP synthases of oxidative phosphorylation in mitochondria and bacteria are very similar.
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