A new study details the minute changes—down to the level of individual atoms—that cause a particular protein to form cell-damaging clumps associated with ALS and other diseases.
hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone.
Now, researchers at the Brown University, have for the first time, described unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes—disease mutations and arginine methylation—on these assemblies.
They have demonstrated atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases of muscle and bone.
Study’s senior author, Nicolas Fawzi of Brown University said, “There is currently no therapy or cure for ALS and frontotemporal dementia. We are pursuing new hypotheses and angles to fight these illnesses.”
“We’re trying to understand why they change behavior and aggregate, and how we can disrupt those processes,”
“We show how small chemical changes — involving only a few atoms — lead to big changes in assembly and disease-associated aggregation,” he said
. “These interactions are more dynamic and less specific than previously thought. A molecule does not take just one shape and bind to one shape but a molecule is flexible and interacts in flexible ways.”Cells divide up their function within distinct cellular structures called organelles, which traditionally thought of as being encased by membranes.
The team studied hnRNPA2, which collects in membrane-less organelles, where it may use its low-complexity domain to stick together, much in the way that water collects into droplets on the outside of a cold soda bottle on a humid summer day. Until the publication of this study, several mechanistic details of how the low-complexity domain of hnRNPA2 worked and how it changed into aggregates in disease were unknown.
Using nuclear magnetic resonance (NMR) spectroscopy, computer simulations and microscopy, the researchers showed how disease mutations and arginine methylation, a functional modification common to a large family of proteins with low-complexity domains, altered the formation of the liquid droplets and their conversion to solid-like states in disease.
“Because these low-complexity domains are too flexible to be directly targeted by standard drugs, finding out how cells use and tame these domains is a potential route to stopping their unwanted assembly in disease,” Fawzi says.
