Electrostatic Repulsion Governs TDP-43 C-terminal Domain Aggregation.

Miguel Mompeán,Avijit Chakrabartty,Emanuele Buratti,Douglas V Laurents,Gregory A Petsko

doi:10.1371/journal.pbio.1002447

Abstract

Electrostatic Repulsion Governs TDP-43 C-terminal Domain Aggregation.

Highlights

One singularly perplexing proposal of Song and coworkers involves the strong pH dependence of the C-terminal domain (CTD)’s aggregation and amyloid formation
TDP-43 is a protein with multiple crucial functions in RNA processing and mRNA-protein particle formation, two processes that are strongly implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) [1]
The results by Lim, Wei, Lu, and Song [2] show that the CTD exists as an intrinsically disordered conformational ensemble, which can be nudged by certain conditions into forming a “hydrogel” or coerced by mutation into adopting hypothetically pathological amyloid structures

Summary

Introduction

One singularly perplexing proposal of Song and coworkers involves the strong pH dependence of the CTD’s aggregation and amyloid formation. The recently published structural characterization by Lim, Wei, Lu, and Song [2] of the complete (residues 262–414) C-terminal domain (CTD) of TDP-43 and three pathologically relevant variants, and the interaction of this region with membrane-mimetics and DNA oligos, builds on our characterization of a smaller Q/N-rich C-terminal segment (residues 341–367) [3,4].

Results

Conclusion