Nav: Home

Cryo-EM images reveal how key biological machine unfolds problem proteins

June 15, 2017

ANN ARBOR -- 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, are scheduled to be 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," said senior study author Daniel Southworth, 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."

The findings suggest there may be similar mechanisms at work more broadly across this important class of proteins, which are called AAA proteins -- for ATPases Associated with diverse cellular Activities. Other members of the class, for example, are involved in DNA replication and repair. AAA proteins are found in plant and animal cells, as well as in bacteria and viruses.

A better understanding of cellular mechanisms can inform scientists' work when they're trying to develop new drugs or delve deeper into biological processes, Southworth said.

"Our study reveals how cells can break apart toxic protein aggregates to make them soluble and restore their function," he said. "If we want to try to harness the power of these molecular machines, it's important to have a clear picture of their mechanics."

Cryo-electron microscopy--or cryo-EM--is an evolving, cutting-edge imaging technology that involves instantaneously freezing proteins in a thin layer of solution. A focused beam of electrons is then used to reveal the shape of these very small, nanometer-sized objects. Specialized computer analysis is needed to combine hundreds of thousands of individual, two-dimensional snapshots in order to assemble the 3-D shape at near-atomic resolution.

The technology can also sort out proteins that are in different stages of a biological process--thus helping to piece together how a biological machine moves, changes and functions.
-end-
The U-M Life Sciences Institute is home to one of the top cryo-EM labs in the country.

The study's co-first authors were Stephanie Gates and Adam Yokom, both graduate students in U-M's Program in Chemical Biology and members of the Southworth lab.

The work was supported by grants and fellowships from Target ALS, American Heart Association, National Institutes of Health, National Science Foundation, Muscular Dystrophy Association, Life Extension Foundation and Packard Center for ALS Research at Johns Hopkins University.

The Science paper is titled "Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104." DOI: 10.1126/science.aan1052

University of Michigan

Related Proteins Articles:

Discovering, counting, cataloguing proteins
Scientists describe a well-defined mitochondrial proteome in baker's yeast.
Interrogating proteins
Scientists from the University of Bristol have designed a new protein structure, and are using it to understand how protein structures are stabilized.
Ancient proteins studied in detail
How did protein interactions arise and how have they developed?
What can we learn from dinosaur proteins?
Researchers recently confirmed it is possible to extract proteins from 80-million-year-old dinosaur bones.
Relocation of proteins with a new nanobody tool
Researchers at the Biozentrum of the University of Basel have developed a new method by which proteins can be transported to a new location in a cell.
Proteins that can take the heat
Ancient proteins may offer clues on how to engineer proteins that can withstand the high temperatures required in industrial applications, according to new research published in the Proceedings of the National Academy of Sciences.
Designer proteins fold DNA
Florian Praetorius and Professor Hendrik Dietz of the Technical University of Munich have developed a new method that can be used to construct custom hybrid structures using DNA and proteins.
The proteins that domesticated our genomes
EPFL scientists have carried out a genomic and evolutionary study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome.
Rare proteins collapse earlier
Some organisms are able to survive in hot springs, while others can only live at mild temperatures because their proteins aren't able to withstand such extreme heat.
How proteins reshape cell membranes
Small 'bubbles' frequently form on membranes of cells and are taken up into their interior.

Related Proteins Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Bias And Perception
How does bias distort our thinking, our listening, our beliefs... and even our search results? How can we fight it? This hour, TED speakers explore ideas about the unconscious biases that shape us. Guests include writer and broadcaster Yassmin Abdel-Magied, climatologist J. Marshall Shepherd, journalist Andreas Ekström, and experimental psychologist Tony Salvador.
Now Playing: Science for the People

#513 Dinosaur Tails
This week: dinosaurs! We're discussing dinosaur tails, bipedalism, paleontology public outreach, dinosaur MOOCs, and other neat dinosaur related things with Dr. Scott Persons from the University of Alberta, who is also the author of the book "Dinosaurs of the Alberta Badlands".