Hi-res view of protein complex shows how it breaks up protein tangles

June 15, 2017, Perelman School of Medicine at the University of Pennsylvania

Misfolded proteins are the culprits behind amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, and other neurodegenerative brain disorders. These distorted proteins are unable to perform their normal functions and cause devastating problems for neurons.

Currently, there is no way to untangle the knotted mass of these proteins to treat .

A high-resolution view of the structure of Hsp104 ( 104), a natural yeast protein nanomachine with six subunits, has been acquired by James Shorter, PhD, an associate professor of Biochemistry and Biophysics in the Perelman School of Medicine at the University of Pennsylvania, and colleagues at the University of Michigan. The Shorter lab has been working on Hsp104 for close to a decade as a way to dismantle harmful protein clumps in disease. The team described their findings in Science this week.

Shorter teamed with colleagues at Michigan who use cutting-edge cryo-EM to provide the clearest image to date of Hsp104 in action. The Penn team provided the highly purified Hsp104 proteins for the study.

"This superb collaboration has yielded the highest resolution picture of Hsp104 caught in the act of processing a protein," Shorter said. "We can now see the moving parts of the Hsp104 complex and how we might tune it to optimally attack neurodegenerative disease proteins."

Hsp104 complex working in a single protein fibril. Credit: Janet Isawa

Hsp104 pulls in proteins it "processes" through a central channel, but scientists had not seen this at high resolution before this study. "With this more-in-focus view, we can see parts of its structure that we want to engineer to make better on-target therapeutics for neurodegenerative diseases," said JiaBei Lin, PhD, co-author and postdoctoral fellow in the Shorter lab.

Normally, Hsp104 is a "disaggregase" enyzme, which dissolves previously aggregated proteins and helps them acquire the correct shape. Although Hsp104 is found in most organisms on the planet, it has no analogue in humans or animals. Shorter asked whether it could be introduced as a drug to dismantle the protein clumps that characterize some diseases. In previous studies, Shorter's lab established that the natural version of Hsp104 is active against neurodegenerative proteins such as alpha-synuclein.

Hsp104 pulls out one polypeptide at a time from the tangles of protein fibrils. The six subunits of the Hsp104 complex hydrolyze ATP as it climbs up the polypeptide strand, which ultimately gets pulled out of the aggregate. Once released, the polypeptide can refold or be degraded.

The team has already made some tweaks to Hsp104 by mutating specific residues to enhance its activity. Working to break up TDP-43, FUS, and alpha-synuclein disease clumps, the reprogrammed Hsp104 pulls these proteins apart better.

"It appears to pull substrates through stepwise, like a ratchet," said senior study author Daniel Southworth, PhD, an assistant professor at the University of Michigan Life Sciences Institute. "We can see how the proteins in the machine rearrange between different states to grab onto the next site on the substrate."

"The study helps us to understand how cells can break apart toxic protein aggregates to restore function," Shorter said. "Finally having a clear picture of this remarkable nanomachine will empower our designs for therapeutic versions that work in humans."

Explore further: Study describes molecular machinery that pulls apart protein clumps

Related Stories

Study describes molecular machinery that pulls apart protein clumps

June 19, 2012
Amyloid fibers are protein aggregates associated with numerous neurodegenerative diseases, including Parkinson's disease, for which there are no effective treatments.

Recommended for you

Aggressive immune cells aggravate Parkinson's disease

July 20, 2018
Parkinson's disease, formerly referred to as "shaking palsy," is one of the most common disorders affecting movement and the nervous system. Medical researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) ...

Researchers trace Parkinson's damage in the heart

July 13, 2018
A new way to examine stress and inflammation in the heart will help Parkinson's researchers test new therapies and explore an unappreciated way the disease puts people at risk of falls and hospitalization.

Study raises doubts on a previous theory of Parkinson's disease

July 6, 2018
Parkinson's disease was first described by a British doctor more than 200 years ago. The exact causes of this neurodegenerative disease are still unknown. In a study recently published in eLife, a team of researchers led ...

Drug protects neurons in Parkinson's disease

June 27, 2018
Systemic treatment of animal models with israpidine, a calcium channel inhibitor, reduced mitochondrial stress that might cause Parkinson's disease, according to a Northwestern Medicine study published in the Journal of Clinical ...

Half of those on Parkinson's drugs may develop impulse control problems

June 20, 2018
Over time, half of the people taking certain drugs for Parkinson's disease may develop impulse control disorders such as compulsive gambling, shopping or eating, according to a study published in the June 20, 2018, online ...

New evidence sheds light on how Parkinson's disease may happen

June 14, 2018
Researchers at Baylor College of Medicine and Texas Children's Hospital have identified unexpected new key players in the development of an early onset form of Parkinson's disease called Parkinsonism. These key players are ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.