SMBp Group Meeting: Justin Lindsay

Thursday Mar 17, 2022, 12:00 PM → 1:00 PM America/New_York

3rd Floor Conference Room/3-Flatiron Institute (162 5th Avenue)

Speaker: Justin Lindsay

Topic: All-atom MD simulations indicate helical regions near poly-Q Tract in Prion-like Domain of Arabidopsis ELF3 Plays Role in Temperature-Sensing

Abstract: Many plants, such as Arabidopsis thaliana, have adapted to sense increasing temperature and respond by up-regulating genes responsible for growth. Recent studies have identified a three-protein circadian clock component, the Evening Complex (EC), a transcription repressor thought to be responsible for integrating temporal information with thermal signals from the environment to quickly enable this genetic response. One of these proteins, ELF3, contains a C-terminal prion-like domain (PrD) responsible for aggregation of the protein into large condensates, removing the complex from DNA and freeing up growth-related genes for transcription. Within this PrD region lies a poly-glutamine repeat of variable length, the size of which has been found to modulate the degree of thermal responsiveness as measured by hypocotyl elongation. Here, we investigate the impact of polyQ tract length on the structure and aggregation dynamics of ELF3-PrDs at a range of temperatures. We characterize ELF3-PrD at the monomer level by utilizing a hierarchical chain-growth method to build atomic resolution ensembles at each condition. Preliminary results indicate three helical short linear motifs (SLiMs) just N-terminal to the polyQ tract are largely responsible for the conformational variability, and thus the function, of the ELF3-PrD ensembles. When polyQ is intact, competitive formation of these SLiMs is observed with propensities becoming nearly equal as temperature increases. In the absence of polyQ, SLiM propensities are temperature-insensitive and match that of the maximum temperature polyQ-containing systems. Additionally contact between one residue pair is found to nearly prohibit formation of two of three SLiMs suggesting a key role in ELF3 function, investigated via replica exchange simulations with solute tempering. We find an aromatic residue in this pair mediates interaction with N-terminal hydrophobic residues to form a globular domain and keeps ELF3 in a ‘tadpole’ shape.  Beyond temperature responsiveness in plants, polyQ-modulated phase separation is implicated in an ever-increasing number of biological processes and diseases, underscoring the general value of a clearer understanding of this mechanism.