June 26, 2019 | David F. Coppedge

ATP Synthase Shows Reason for ‘Slippage’

The engine of life shows more engineering finesse with each new discovery.

ATP synthase is surely one of the most amazing molecular machines we have reported on. Tiny but mighty, this rotary engine that runs on protons released from the food we eat is incredibly efficient, fast, and complicated. Being essential for all life, it challenges any kind of step-wise evolutionary origin. But for years, scientists wondered about a mismatch between its two halves.

The motor consists of two parts, called F0 (which rotates powered by proton motive force), and F1 (where ATP is synthesized, yielding 3 ATP per revolution). The puzzling mismatch comes from the number of units in these two halves. Different species of ATP synthase have 8 to 17 “c subunits” in F0 (usually 10 to 12) that make up the carousel that rotates and turns the “gamma” central stalk, which acts like a camshaft connecting the two parts. The F1 part, though, has three pairs of two units. For every complete rotation of F0, with a corresponding rotation of the camshaft, three ATP are produced in F1. Why is there not a nice integer division between the two? How can 11 c subunits in F0 correspond to 3 ATP molecules in F1? Is there some slippage in the mechanism?

ATP synthase is a rotary motor that generates 3 ATP per revolution.

A new paper in Science Magazine sheds more light on this puzzle. In “Rotary substates of mitochondrial ATP synthase reveal the basis of flexible F1-Fo coupling,” Murphy et al. address the issue: “An enduring question is how the stoichiometrically mismatched c ring in Fo (composed of 8 to 17 c subunits) and the three-fold symmetric F1 head are efficiently coupled.” The paper summary announces a reason for this mismatch that makes ATP synthase appear more and more like a “well-oiled machine”—

They solved high-resolution cryo–electron microscopy structures of the ATP synthase complex, extracting 13 rotational substates. This collection of structures revealed that the rotation of the Fo ring and central stalk is coupled with partial rotations of the F1 head. This flexibility may enable the head to better couple continuous rotation with discrete ATP synthesis events.

In other words, there is a slight rotation of the F1 head that not only synchronizes the two halves, but may actually contribute to the motor’s productivity. For those who like jargon,

We find that the F1 head rotates together with the central stalk and c ring through approximately 30°, or one c subunit, at the beginning of each 120° step. Flexible coupling of the F1 head to the Fo motor is mediated primarily by a hinge at the interdomain link of the oligomycin sensitivity–conferring protein (OSCP) subunit that joins the F1 head to the peripheral stalk. The extended two-helix bundle of the central stalk γ subunit interacts with the catch-loop region of one β subunit of the F1 head. The resulting mechanism of flexible coupling is likely to be conserved [i.e., unevolved] in other F1-Fo ATP synthases. Our results provide much-needed context to a wealth of published data indicating that OSCP is a hub of metabolic control in the cell.

This is an elegant design. It basically provides an interface between disparate parts, like a human-engineered”universal mount” with a flexible connector that can work with different models. The authors summarize this as follows:

In ATP synthases, the F1 catalytic head can accompany the rotor through a rotation of ~30° at the beginning of each ~120° step. This movement allows flexible coupling of F1 and Fo. The interdomain hinge of OSCP facilitates flexible coupling and makes this subunit an apposite [def. “suitable; well-adapted; pertinent; relevant; apt”] point for the regulation of ATP synthesis.

In addition, the authors found a metal ion (probably Zn+2) that may be involved in translating the proton flow into a torque. That’s another mysterious aspect of ATP synthase: how does a flow of protons actually turn the F0 motor? It’s been hard to tell, because that part of the engine is embedded in the membrane. They conclude, “A conserved [unevolved] metal ion in the proton access channel may synchronize c-ring protonation with rotation.” This hypothesis may require additional research. It might also be illuminating to investigate the diversity c subunits between species, to see whether there are reasons for 8, 10, 12, or 17 subunits depending on the environment, or whether they are due to neutral mutations which the conserved “flexible coupling” is designed to accommodate.

Needless to say, the authors did not mention “evolution” in the paper.

ATP synthase is a molecular machine you can use to “wow” your friends. “Did you know that you are running on rotary engines?” In simple terms, describe this waterwheel-like action that runs a mechanism that snaps ATP together, making 3 ATP per revolution. Tell them it is one of the most efficient engines ever discovered, but add that it is on the order of billionths of a meter in size. Tell them the protons come from the food you just ate, and that quadrillions of these little engines are spinning at over 6,000 RPM inside you right now. It might lead to some lively discussions about origins.



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