Cargando…

Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation

[Image: see text] Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure...

Descripción completa

Detalles Bibliográficos
Autores principales: Tan, Cheng, Niitsu, Ai, Sugita, Yuji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052238/
https://www.ncbi.nlm.nih.gov/pubmed/37006777
http://dx.doi.org/10.1021/jacsau.2c00646
_version_ 1785015113186541568
author Tan, Cheng
Niitsu, Ai
Sugita, Yuji
author_facet Tan, Cheng
Niitsu, Ai
Sugita, Yuji
author_sort Tan, Cheng
collection PubMed
description [Image: see text] Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure (Hero) proteins, was shown to protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero proteins protect other proteins from aggregation remain unknown. In this study, we performed multiscale molecular dynamics (MD) simulations of Hero11, a Hero protein, and the C-terminal low-complexity domain (LCD) of the transactive response DNA-binding protein 43 (TDP-43), a client protein of Hero11, under various conditions to examine their interactions with each other. We found that Hero11 permeates into the condensate formed by the LCD of TDP-43 (TDP-43-LCD) and induces changes in conformation, intermolecular interactions, and dynamics of TDP-43-LCD. We also examined possible Hero11 structures in atomistic and coarse-grained MD simulations and found that Hero11 with a higher fraction of disordered region tends to assemble on the surface of the condensates. Based on the simulation results, we have proposed three possible mechanisms for Hero11’s regulatory function: (i) In the dense phase, TDP-43-LCD reduces contact with each other and shows faster diffusion and decondensation due to the repulsive Hero11–Hero11 interactions. (ii) In the dilute phase, the saturation concentration of TDP-43-LCD is increased, and its conformation is relatively more extended and variant, induced by the attractive Hero11–TDP-43-LCD interactions. (iii) Hero11 on the surface of small TDP-43-LCD condensates can contribute to avoiding their fusion due to repulsive interactions. The proposed mechanisms provide new insights into the regulation of biomolecular condensation in cells under various conditions.
format Online
Article
Text
id pubmed-10052238
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher American Chemical Society
record_format MEDLINE/PubMed
spelling pubmed-100522382023-03-30 Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation Tan, Cheng Niitsu, Ai Sugita, Yuji JACS Au [Image: see text] Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure (Hero) proteins, was shown to protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero proteins protect other proteins from aggregation remain unknown. In this study, we performed multiscale molecular dynamics (MD) simulations of Hero11, a Hero protein, and the C-terminal low-complexity domain (LCD) of the transactive response DNA-binding protein 43 (TDP-43), a client protein of Hero11, under various conditions to examine their interactions with each other. We found that Hero11 permeates into the condensate formed by the LCD of TDP-43 (TDP-43-LCD) and induces changes in conformation, intermolecular interactions, and dynamics of TDP-43-LCD. We also examined possible Hero11 structures in atomistic and coarse-grained MD simulations and found that Hero11 with a higher fraction of disordered region tends to assemble on the surface of the condensates. Based on the simulation results, we have proposed three possible mechanisms for Hero11’s regulatory function: (i) In the dense phase, TDP-43-LCD reduces contact with each other and shows faster diffusion and decondensation due to the repulsive Hero11–Hero11 interactions. (ii) In the dilute phase, the saturation concentration of TDP-43-LCD is increased, and its conformation is relatively more extended and variant, induced by the attractive Hero11–TDP-43-LCD interactions. (iii) Hero11 on the surface of small TDP-43-LCD condensates can contribute to avoiding their fusion due to repulsive interactions. The proposed mechanisms provide new insights into the regulation of biomolecular condensation in cells under various conditions. American Chemical Society 2023-02-24 /pmc/articles/PMC10052238/ /pubmed/37006777 http://dx.doi.org/10.1021/jacsau.2c00646 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Tan, Cheng
Niitsu, Ai
Sugita, Yuji
Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title_full Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title_fullStr Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title_full_unstemmed Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title_short Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
title_sort highly charged proteins and their repulsive interactions antagonize biomolecular condensation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10052238/
https://www.ncbi.nlm.nih.gov/pubmed/37006777
http://dx.doi.org/10.1021/jacsau.2c00646
work_keys_str_mv AT tancheng highlychargedproteinsandtheirrepulsiveinteractionsantagonizebiomolecularcondensation
AT niitsuai highlychargedproteinsandtheirrepulsiveinteractionsantagonizebiomolecularcondensation
AT sugitayuji highlychargedproteinsandtheirrepulsiveinteractionsantagonizebiomolecularcondensation