Hand over hand. That's how new, near-atomic resolution, 3-D snapshots show that a key biological machine unfolds a ribbon of protein through its central channel.
The machine is a protein complex called a disaggregase. It helps pull apart the threads of problematic, misfolded proteins that can accumulate and become toxic to cells—like the amyloid proteins associated with Alzheimer's disease. The recovered proteins are then either refolded or destroyed to prevent dysfunction and maintain balance in the cell.
The structures were determined by a University of Michigan-led team using cryo-electron microscopy, and done in collaboration with researchers at the University of Pennsylvania. Their findings, which required about 200,000 hours of computation, were published June 15 in Science
Scientists previously understood what the disaggregase did, but not precisely how it worked.
"It appears to pull substrates through stepwise, like a ratchet," says senior study author Daniel Southworth, Ph.D., an assistant professor at the U-M Life Sciences Institute, where his lab is located, and in the Department of Biological Chemistry at the U-M Medical School. "It's a very orderly process that moves around the machine's six subunits. We can see how the proteins in the machine rearrange between different states to grab onto the next site on the substrate. There were several models that had been proposed for how this happens — and now, for the first time, we can start to see what's actually occurring."