Abstract
Adenosine triphosphate (ATP), the chemical energy currency of biology, is synthesized in eukaryotic cells primarily by the mitochondrial ATP synthase. ATP synthases operate by a rotary catalytic mechanism where proton translocation through the membrane-inserted FO region is coupled to ATP synthesis in the catalytic F1 region via rotation of a central rotor subcomplex. We report here single particle electron cryomicroscopy (cryo-EM) analysis of the bovine mitochondrial ATP synthase. Combining cryo-EM data with bioinformatic analysis allowed us to determine the fold of the a subunit, suggesting a proton translocation path through the FO region that involves both the a and b subunits. 3D classification of images revealed seven distinct states of the enzyme that show different modes of bending and twisting in the intact ATP synthase. Rotational fluctuations of the c8-ring within the FO region support a Brownian ratchet mechanism for proton-translocation-driven rotation in ATP synthases.
Highlights
In the mitochondria of eukaryotes, adenosine triphosphate (ATP) is produced by the ATP synthase, a ~600 kDa membrane protein complex composed of a soluble catalytic F1 region and a membraneinserted FO region
Predicting the path of protons through membrane protein complexes has proven difficult, even in cases where high-resolution atomic models including bound water molecules are available from Xray crystallography (Hosler et al, 2006)
Features in the structure of the bovine mitochondrial FO region suggest a possible path for proton translocation similar to a model put forward based on the structure of the Polytomella sp
Summary
In the mitochondria of eukaryotes, adenosine triphosphate (ATP) is produced by the ATP synthase, a ~600 kDa membrane protein complex composed of a soluble catalytic F1 region and a membraneinserted FO region. The subunit composition is a3b3gde for the F1 region with subunits a, e, f, g, A6L, DAPIT, a 6.8 kDa proteolipid, two membrane-inserted a-helices of subunit b, and the c8-ring forming the FO region (Walker, 2013). 85% of the structure of the complex is known at high resolution from X-ray crystallography of constituent proteins, which have been assembled into a mosaic structure within the constraints of a cryo-EM map at 18 Aresolution (Walker, 2013; Baker et al, 2012)
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