Atomistic Insights into A315E Mutation-Enhanced Pathogenicity of TDP-43 Core Fibrils

ACS Chem Neurosci. 2022 Sep 21;13(18):2743-2754. doi: 10.1021/acschemneuro.2c00416. Epub 2022 Sep 2.

Abstract

The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is implicated in amyotrophic lateral sclerosis (ALS), and some hereditary mutations localized in the low complexity domain (LCD) facilitate the formation of pathogenic TDP-43 fibrils. A recent cryo-EM study reported the atomic-level structures of the A315E TDP-43 LCD (residues 288-319, TDP-43288-319) core fibril in which the protofilaments have R-shaped structures and hypothesized that A315E U-shaped protofilaments can readily convert to R-shaped protofilaments compared to the wild-type (WT) ones. There are no atomic structures of WT protofilaments available yet. Herein, we performed extensive all-atom explicit-solvent molecular dynamics simulations on A315E and WT protofilaments starting from both the cryo-EM-determined R-shaped and our constructed U-shaped structures. Our simulations show that WT protofilaments also adopt the R-shaped structures but are less stable than their A315E counterparts. Except for R293-E315 salt bridges, N312-F316 hydrophobic interactions and F316-F316 π-π stacking interactions are also crucial for the stabilization of the neck region of the R-shaped A315E protofilaments. The loss of R293-E315 salt bridges and the weakened interactions of N312-F316 and F316-F316 result in the reduced stability of the R-shaped WT protofilaments. Simulations starting from U-shaped folds reveal that A315E protofilaments can spontaneously convert to the cryo-EM-derived R-shaped protofilaments, whereas WT protofilaments convert to R-shape-like structures with remodeled neck regions. The R-shape-like WT protofilaments could act as intermediate states slowing down the U-to-R transition. This study reveals that A315E mutation can not only enhance the structural stability of the R-shaped TDP-43288-319 protofilaments but also promote the U-to-R transition, which provides atomistic insights into the A315E mutation-enhanced TDP-43 pathogenicity in ALS.

Keywords: A315E mutation; TDP-43; U-to-R transition; molecular dynamics simulation; molecular mechanism; protofilaments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • DNA-Binding Proteins / chemistry*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Humans
  • Mutation
  • Solvents
  • Virulence

Substances

  • DNA-Binding Proteins
  • Solvents
  • TARDBP protein, human