Structure of ATPase, the world's smallest turbine, solved
First complete structure of mammalian F1Fo ATP-synthase

Date:
September 14, 2020
Source:
Institute of Science and Technology Austria
Summary:
The chemical ATP, adenosine triphosphate, is the fuel that powers
all life. Despite ATP's central role, the structure of the enzyme
generating ATP, F1Fo-ATP synthase, in mammals, including humans, has
not been known so far. Now, scientists report the first complete
structure of the mammalian F1Fo-ATP synthase. This structure
also settles a debate on how the permeability transition pore, a
structure involved in cell death, cancer, and heart attacks, forms.



FULL STORY ==========================================================================
ATP synthase is also referred to as complex V of the respiratory chain,
a series of protein complexes in the membrane of mitochondria. This
respiratory chain creates a proton gradient, which the ATP synthase uses
to make ATP.

Previously, Sazanov was the first to solve the protein structure of
bacterial complex I, and the first to solve the structure of a mammalian complex I. In the new study, Sazanov and lab members Gergely Pinke and
Long Zhou turned to mammalian complex V, the final unsolved structure
in the mammalian respiratory chain. "F1Fo-ATP synthase is one of the
most important enzymes on Earth. It provides energy for most life forms, including us humans, but until now, we didn't know fully how it works," explains Sazanov.


========================================================================== Rotation muddies the picture As the structure of the mushroom-like F1
soluble domain is known already, Sazanov and his team looked particularly
at the Fo domain, embedded in the mitochondrial membrane. Here, protons
are translocated at the interface between the so-called c ring, a ring
made up of identical protein subunits, and the rest of Fo. Protons are
moved across the membrane as each c subunit picks up a proton on one side
of the membrane, rotates with the ring, and releases the proton on the
other side. This c-ring is attached to the central shaft of F1 and its
rotation generates ATP within F1. To solve the structure of the Fo domain
and the entire complex, the researchers studied the enzyme from sheep mitochondria using cryo-electron microscopy. And here, ATP synthase poses
a special problem: because it rotates, ATP synthase can stop in three main positions, as well as in substates. "It is very difficult to distinguish between these positions, attributing a structure to each position ATP
synthase can take. But we managed to solve this computationally to build
the first complete structure of the enzyme," Sazanov adds.

Location of the permeability transition pore found In their
high-resolution structure of Fo, the researchers found that the c-ring is plugged by two lipids, one from each side of the membrane. While the top (facing F1) lipid rotates along with the shaft, the bottom lipid does not rotate, as it is likely connected to the Fo domain via a "hook apparatus."
This newly uncovered structure sheds light on a controversy in biology:
how and where the so-called permeability transition pore opens. This
pore is linked with cell death, and opens for example during strokes and
heart attacks. So far, it was known that the pore forms in mitochondria
in response to high levels of Calcium, but the pore's exact location
remained unknown. Now, using the fully solved structure of F1Fo, Sazanov
and his group can describe how the pore forms in F1Fo-ATP synthase:
When Calcium binds in the F1 subunit, a large conformational change is
induced. The complex has to accommodate this change, and in doing so,
pulls on the hook apparatus. The apparatus in turn pulls out the lipid
plug on the bottom side of the Fo, initiating pore opening. "When the
pore is open for a longer period of time, the c-ring is destabilized and
pore formation becomes irreversible," explains Sazanov. "This model is consistent with all available data from mutants. To be fully sure that
this is how the permeability transition pore forms, one would need to
solve the structure of ATP synthase during Calcium-induced transitions,
which we are doing now."

========================================================================== Story Source: Materials provided by Institute_of_Science_and_Technology_Austria. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Gergely Pinke, Long Zhou, Leonid A. Sazanov. Cryo-EM structure
of the
entire mammalian F-type ATP synthase. Nature Structural & Molecular
Biology, 2020; DOI: 10.1038/s41594-020-0503-8 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/09/200914114134.htm

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