Dartmouth researchers have found that some proteins turn into liquid droplets on the way to becoming toxic solids implicated in neurodegenerative diseases and other genetic disorders.
The findings, along with a series of related studies by scientists at other institutions, appear in the journal Molecular Cell.
The Dartmouth researchers studied proteins that have a massive expansion of a single amino acid, glutamine, typically associated with toxic protein solids. For example, neurodegenerative-linked proteins such as those in Huntington’s disease have these amino acids, which makes the protein sticky. The researchers found that proteins like this undergo a transition into liquid droplets on the way to becoming toxic, fibrous solids. These liquid droplets are similar to the ones made when oil and vinegar are mixed to make salad dressing. The researchers suspect that cells use this liquid state for normal physiology, but under certain conditions the proteins transition again from liquid to toxic solids. These kinds of droplets have also been called “membrane-free” organelles because they lack a barrier and are highly dynamic unlike many organelles such as mitochondria or nuclei.
“We found that RNA, the molecule traditionally thought as the intermediate between DNA and protein, has a potent role in driving the formation of the liquid states,” says senior author Amy Gladfelter, an associate professor of biological sciences. “They can drive the formation of droplets and give distinct physical properties to the droplets, which we think is important for how they are spatially arranged and function in the cell. It’s exciting that this is an example of RNA encoding physical properties of these compartments or drops rather than just encoding proteins.”
The results are important because the human genome is filled with proteins that have similar sequences and almost all understanding of these proteins so far has focused on pathological states.
“Our work, along with the other recent papers, find a form of these proteins that is relevant to normal cell function and yet takes advantage of the very sequences that are linked to diseases for their normal functions,” Gladfelter says. “This type of mechanistic understanding of the protein’s normal function is critical for understanding and treating a myriad of diseases linked to protein aggregation.”
About this genetics and neurology research
Source: John Cramer – Dartmouth College Image Source: The image is in the public domain Original Research:Abstract for “RNA Controls PolyQ Protein Phase Transitions” by Huaiying Zhang, Shana Elbaum-Garfinkle, Erin M. Langdon, Nicole Taylor, Patricia Occhipinti, Andrew A. Bridges, Clifford P. Brangwynne, and Amy S. Gladfelter in Molecular Cell. Published online September 17 2015 doi:10.1016/j.molcel.2015.09.017
Highlights •RNA drives phase transition of Whi3, an RNA-binding protein with a long polyQ tract •RNA alters Whi3 droplet viscosity, dynamics, and their propensity to fuse •Different target mRNAs drive Whi3 to form droplets with distinct properties •Whi3 droplets mature and appear fibrillar over time
Summary Compartmentalization in cells is central to the spatial and temporal control of biochemistry. In addition to membrane-bound organelles, membrane-less compartments form partitions in cells. Increasing evidence suggests that these compartments assemble through liquid-liquid phase separation. However, the spatiotemporal control of their assembly, and how they maintain distinct functional and physical identities, is poorly understood. We have previously shown an RNA-binding protein with a polyQ-expansion called Whi3 is essential for the spatial patterning of cyclin and formin transcripts in cytosol. Here, we show that specific mRNAs that are known physiological targets of Whi3 drive phase separation. mRNA can alter the viscosity of droplets, their propensity to fuse, and the exchange rates of components with bulk solution. Different mRNAs impart distinct biophysical properties of droplets, indicating mRNA can bring individuality to assemblies. Our findings suggest that mRNAs can encode not only genetic information but also the biophysical properties of phase-separated compartments.
“RNA Controls PolyQ Protein Phase Transitions” by Huaiying Zhang, Shana Elbaum-Garfinkle, Erin M. Langdon, Nicole Taylor, Patricia Occhipinti, Andrew A. Bridges, Clifford P. Brangwynne, and Amy S. Gladfelter in Molecular Cell. Published online September 17 2015 doi:10.1016/j.molcel.2015.09.017