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Scripps and Illinois researchers discovered in alternate pathway by which the protein TTR dissociates into smaller subunits and unfolds, causing amyloidosis. Instead of first breaking into two intermediate parts like the typical pathway, illustrated in red, the protein directly disassembles into its four component subunits by the alternate pathway, shown in blue.
Graphic Credit: Jan-Hannes Schäfer, Scripps Research
Scientific Frontline: Extended "At a Glance" Summary: Alternate Unfolding Pathway of Transthyretin (TTR) Protein
The Core Concept: Researchers have discovered a previously unknown, alternative pathway by which the transthyretin (TTR) protein dissociates and unfolds, potentially leading to amyloidosis.
Key Distinction/Mechanism: Instead of breaking into two-unit intermediates before fully unfolding, the alternate pathway involves the four-unit TTR protein disassembling directly into its four component subunits.
Origin/History: Published in September 2026 in the Proceedings of the National Academy of Sciences by researchers from Scripps Research and the University of Illinois Urbana-Champaign.
Major Frameworks/Components:
- TTR variants that utilize this alternate pathway include mutations associated with rare hereditary forms of amyloidosis, particularly those affecting the brain and central nervous system.
- The alternative unfolding pathway is favored under acidic conditions, similar to the environment within lysosomes.
- Energy landscape theory, which proposed parallel pathways for protein folding and unfolding since the 1990s, is supported by this physical demonstration.
Branch of Science: Biochemistry, Molecular Biology, Biophysics.
Future Application: The discovery opens new avenues for developing drugs that target specific amyloidosis pathways, particularly for patients with rare mutations where current medications (like tafamidis) may be less effective or counterproductive.
Why It Matters: Uncovering this parallel pathway is crucial for understanding how proteins misfold and aggregate in degenerative diseases, potentially improving treatment outcomes for rare and deadly forms of systemic amyloidosis.
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| Illinois professor Martin Gruebele. Photo Credit: Fred Zwicky |
The protein transthyretin can unfold and dissociate in a previously unknown way, possibly contributing to a rare and deadly form of amyloidosis, new findings from Scripps Research and the University of Illinois Urbana-Champaign reveal.
TTR is a protein that helps transport vitamin A and the thyroid hormone thyroxine in the blood, cerebrospinal fluid, and the eye. Over time, its four-unit structure splits into pieces that can misfold and clump together, causing one of the most common forms of systemic amyloidosis in humans, particularly in the heart and nervous systems.
One of the standard treatments, a drug called tafamidis, works by helping TTR stay intact and slowing how it normally unfolds. However, the Scripps and Illinois researchers have discovered a second, previously unknown TTR unfolding pathway that may cause protein aggregation in some rare hereditary forms of the disease.
“Any new pathway by which a protein could unfold, and thus subsequently form amyloids, is of interest because it may not react to drugs in the same way as the previously known pathway,” said Martin Gruebele, a University of Illinois professor emeritus of chemistry and co-corresponding author of the paper. “This finding also furthers our understanding of protein folding and unfolding. Parallel pathways have been proposed by energy landscape theory since the 1990s, yet very few cases have been clearly identified.”
“TTR is, as far as we know, the first time multiple pathways have been shown in a multimeric protein where dissociation and unfolding go hand in hand,” said Scripps researcher Marcus Jäger, the first author of the paper.
To uncover the alternative pathway, the researchers tested more than 100 TTR variants, measuring how quickly each unfolded across a range of conditions. They supported their findings using cryogenic electron microscopy and previously published X-ray crystal structures.
The results reveal that some variants of TTR have a second unfolding route in which the four-unit structure falls apart more directly, without the two-unit intermediates formed in the traditional pathway. The TTR variants that can unfold by the alternative pathway include some that cause amyloidosis in the brain.
“We need to understand whether this alternative pathway can lead to TTR aggregation in the cerebrospinal fluid, which could potentially translate into worse outcomes for patients carrying these rare mutations who take the current medications,” said study leader Jeffery Kelly, the H. Lutcher Brown Professor of Chemistry at Scripps Research, who also co-developed tafamidis.
The alternative pathway is also favored under acidic conditions—the environment found inside lysosomes, the cellular organelles where proteins are broken down and recycled at the end of their life cycle.
“This route probably evolved so TTR can be degraded, which is important, but can also have side effects,” Gruebele said. “If TTR could dissociate and unfold via a new pathway in that environment, this could open it up to aggregation and amyloid formation.”
For people with the most common types of TTR amyloidosis, the alternative pathway appears too slow under normal conditions to compete with the known pathway. But certain disease-associated mutations appear to make the new pathway more accessible, even at normal blood acidity, Kelly said.
“More research is needed, but this study opens up a new direction in the field of drugs targeting specific amyloidosis pathways,” said Gruebele. “At least we have one of several possible smoking guns to look at.”
More broadly, the findings could inform how scientists think about other proteins linked to degenerative disease, according to Kelly.
“This is an amazing example of using traditional biophysics to conclusively demonstrate that parallel pathways can govern the folding and unfolding of a protein, which historically has been hard to demonstrate experimentally,” Kelly said.
Funding: This work was supported by the National Institutes of Health grant R01 DK046335 and a postdoctoral fellowship from the German Research Foundation.
Published in journal: Proceedings of the National Academy of Sciences
Title: Transthyretin can denature by an alternative pathway
Authors: Marcus Jäger, Jan-Hannes Schäfer, Gabriel C. Lander, Evan T. Powers, Martin Gruebele, and Jeffery W. Kelly
Source/Credit: University of Illinois Urbana-Champaign | Liz Ahlberg Touchstone
Edited by: Scientific Frontline
Reference Number: bchm091026_01
