Working together to form liquid droplets

What is it about?

TDP-43 is a protein which participates in various gene-regulatory processes by attaching to certain types of RNA molecules within the cell nucleus. A specific part of TDP-43 called the C-terminal domain (CTD) tends to form solid-like clumps in test-tube experiments and inside cells. The formation of TDP-43 clumps in nerve cells of the brain is often associated with certain aging-related diseases like amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). More recently, it has been shown that CTD can also form liquid-like droplets by a process called liquid-liquid phase separation. Interestingly, these droplets can change over time to form solid-like clumps. Previous studies have found that the central region (CR) within CTD, is hydrophobic (water-repelling) and has a well-defined, helical structure. An interesting property of CR is its ability to bind copies of itself on other CTD molecules to form larger assemblies called oligomers. The formation of oligomeric assemblies is an essential intermediate step for the phase separation of CTD. In addition to CR, the surrounding regions (IDRs) which are unstructured, were also independently shown to promote phase separation and subsequent clumping. Nevertheless, how the different CTD regions function together and their relative importance towards the process of phase separation has remained unclear. In this study, we used both computer simulations and test-tube experiments to understand the relative contributions of CR and IDRs towards the formation of CTD droplets. We found that certain hydrophobic amino acids in the IDRs directly strengthen the tendency of CR to form oligomers and thereby undergo phase separation. This is achieved through short-lived (transient) interactions between the IDRs of different CTD molecules.

Featured Image

Photo by Nithya Ramanujam on Unsplash

Photo by Nithya Ramanujam on Unsplash

Why is it important?

Our research provides insights into an interesting and unconventional mechanism by which TDP-43 CTD molecules can assemble to form liquid-like droplets. Such insights are likely to be important for understanding the function of TDP-43 in brain tissues and aid in the development of drugs for diseases related to its malfunction.