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, Amandeep and Bharathi, Vidhya and Tiwari, Vikas Ramyagya and Abhishek, Suman and Deeksha, Waghela and Mahawar, Usha Saraswat and Raju, Gembali and Singh, Sandeep Kumar and Prabusankar, Ganesan and Rajakumara, Eerappa and Patel, Basant K. (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
Girdhar, A.UNSPECIFIED
Bharathi, V.UNSPECIFIED
Tiwari, V.R.UNSPECIFIED
Abhishek, S.UNSPECIFIED
Diksha, S.UNSPECIFIED
Mahawar, U.S.UNSPECIFIED
Raju, G.UNSPECIFIED
Singh, S.K.UNSPECIFIED
Prabusankar, G.UNSPECIFIED
Rajakumara, E.UNSPECIFIED
Patel, B.K.UNSPECIFIED
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: 21 Jun 2021 10:24
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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