Researchers at the Weizmann Institute of Science have elucidated the mechanism by which AAA+ molecular machines unravel misfolded proteins.
Their study, published in Nature Communications, reveals that these machines operate as energy-efficient Brownian motors rather than using a hand-over-hand pulling mechanism.
Key Findings
- AAA+ machines consist of six protein subunits arranged in a ring with a central channel.
- They convert chemical energy from ATP into mechanical work to thread protein chains through the channel.
- Using fluorescent sensors, researchers tracked the real-time movement of a protein through the machine.
The protein segment moved through the channel within milliseconds, while ATP breakdown takes over half a second, indicating high energy efficiency.
- Experiments with inactive ATP analogs and reduced ATP concentration showed that energy is used to initiate threading and maintain direction, but not to forcibly pull the chain.
- The proposed mechanism is a Brownian motor: random motion is biased in one direction by the machine's structure, with loops in the channel acting like revolving door wings.
- In failure events, proteins moved back and forth before exiting from the same entrance, suggesting no large energy fluctuations inside the channel.
Significance
- The study explains how cells perform quality control on proteins, with implications for diseases like neurodegeneration and cancer.
- The Brownian mechanism may also apply to other functions of AAA+ machines, such as transporting proteins and genetic material across membranes.
- Insights could inspire the design of more efficient artificial molecular machines.