489019 Effect of Residual Secondary Structure Propensity on Liquid-Liquid Phase Separation of Tdp-43

Gregory L. Dignon1, Gul H. Zerze1, Nicolas Fawzi2, Young C. Kim3 and Jeetain Mittal1, (1)Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA, (2)Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI, (3)Center for Computational Materials Science, Naval Research Laboratory, Washington, DC

TDP-43 is a partially disordered protein involved in RNA metabolism with implications in the disease pathology of amyotrophic lateral sclerosis, and frontotemporal dementia (ALS/FTD). It is a 414-residue protein containing multiple folded and disordered domains, capable of assembling into liquid droplets composed primarily of protein. Most notable is its disordered 141-residue C-terminal prion-like domain, where most ALS/FTD-associated mutations occur.This region also undergoes transient helix formation in solution which may contribute in some way to the self-assembly behavior. Our goal is to elucidate the role of the disordered domain in the formation and stability of these assemblies, and how transient helicity may promote, or inhibit such behavior. Using a newly developed coarse-grained model for multiprotein assembly, we are able to compute thermodynamic phase behavior of TDP-43 and how it is perturbed by changes in residual helicity due to disease or designed mutations. Our results highlight important functional role for helical structures populated in the TDP-43 equilibrium ensemble in mediating interpeptide contacts and stabilizing liquid droplets.


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See more of this Session: Thermodynamics of Biomolecular Folding and Assembly
See more of this Group/Topical: Engineering Sciences and Fundamentals