Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4

Girdhar, A. and Rajakumara, E. and et al, . (2020) Computational insights into mechanism of AIM4-mediated inhibition of aggregation of TDP-43 protein implicated in ALS and evidence for in vitro inhibition of liquid-liquid phase separation (LLPS) of TDP-432C-A315T by AIM4. International Journal of Biological Macromolecules, 147. pp. 117-130. ISSN 01418130

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Abstract

TDP-43 is an RNA/DNA-binding protein which is also implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) disease. TDP-43's cytoplasmic mis-localization, liquid-liquid phase separation (LLPS) due to RNA depletion and aggregation, are proposedly important TDP-43-toxicity causing mechanisms. So far, therapeutic options for ALS are extremely ineffective hence, multi-faceted approaches such as targeting the oxidative stress and inhibiting the TDP-43's aggregation, are being actively pursued. Recently, we have identified an acridine derivative, AIM4, as an anti-TDP-43 aggregation molecule however, its mechanism is not deciphered. Here, we have utilized computational tools to examine binding site(s) of AIM4 in the TDP-43 structure and compared with other relevant compounds. We find that AIM4 has a binding site in the C-terminal amyloidogenic region (aa: 288–319), with Gly-288 & Phe-289 residues which are also important for TDP-43's LLPS. Importantly, alike to previously reported effects of RNA, AIM4 could also inhibit the in vitro LLPS of a C-terminal fragment TDP-432C bearing an A315T familial mutation. Furthermore, isothermal titration calorimetry (ITC) data also support the binding of AIM4 to TDP-432C-A315T. This antagonism of AIM4 towards TDP-43's LLPS and presence of binding site of AIM4 on TDP-43 support AIM4's potential to be an important molecule towards ALS therapeutic research.

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IITH Creators:
IITH CreatorsORCiD
Rajakumara, EerappaUNSPECIFIED
Item Type: Article
Uncontrolled Keywords: amyotrophic lateral sclerosis; Article; binding affinity; carboxy terminal sequence; computer model; concentration response; controlled study; crystal structure; drug binding site; drug mechanism; drug protein binding; drug structure; in vitro study; isothermal titration calorimetry; ligand binding; molecular docking; molecular dynamics; phase separation; protein aggregation; protein aggregation inhibition; protein expression; protein structure; amyotrophic lateral sclerosis; chemistry; computer simulation; human; metabolism; protein conformation; protein stability; thermodynamics
Subjects: Computer science
Chemistry
Chemistry > Inorganic chemistry
Chemistry > Organic chemistry
Divisions: Department of Chemistry
Depositing User: . LibTrainee 2021
Date Deposited: 21 Jun 2021 10:24
Last Modified: 18 Feb 2022 06:40
URI: http://raiith.iith.ac.in/id/eprint/7961
Publisher URL: http://doi.org/10.1016/j.ijbiomac.2020.01.032
OA policy: https://v2.sherpa.ac.uk/id/publication/12553
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