The physical forces mediating self-association and phase-separation in the C-terminal domain of TDP-43.

摘要: The TAR DNA-binding protein of 43kDa (TDP-43) has been identified as the main component amyotrophic lateral sclerosis (ALS) cytoplasmic inclusions. link between this proteinopathy and TDP-43's intrinsically disordered C-terminal domain is well known, but recently also, shown to be involved in formation membraneless organelles that mediate functions. mechanisms underpin liquid-liquid phase separation (LLPS) these undergo remain elusive. Crucially though, factors may key understanding delicate balance physiological pathological In study, we used nuclear magnetic resonance spectroscopy optical methods demonstrate an α-helical centre (residues 320-340) related protein's self-association LLPS. Systematically analysing ALS-related TDP-43 mutants (G298S, M337V, Q331K) different buffer conditions at temperatures, prove driven by hydrophobic interactions inhibited electrostatic repulsion. Based on findings, rationally introduced a mutant, W334G, mutant disrupts LLPS without disturbing propensity. This tryptophan serve residue