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Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration

The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM do...

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Detalles Bibliográficos
Autores principales: Liu, Wei, Li, Chaoqun, Shan, Jiankai, Wang, Yan, Chen, Guangju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371369/
https://www.ncbi.nlm.nih.gov/pubmed/34457335
http://dx.doi.org/10.1098/rsos.210160
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author Liu, Wei
Li, Chaoqun
Shan, Jiankai
Wang, Yan
Chen, Guangju
author_facet Liu, Wei
Li, Chaoqun
Shan, Jiankai
Wang, Yan
Chen, Guangju
author_sort Liu, Wei
collection PubMed
description The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM domains of TDP-43 using molecular dynamics simulations in combination with the protein–protein docking. Our results showed that the formations of the dimer models are mainly achieved by the interactions of the RRM1 domains. The parallel β-sheet layers between the RRM1 domains provide most of the binding sites in these oligomer models, and thus play an important role in the aggregation process. The approaching of the parallel β-sheet layers from small oligomer models gradually expand to large ones through the allosteric communication between the α1/α2 helices of the RRM1 domains, which maintains the binding affinities and interactions in the larger oligomer models. Using the repeatable-superimposing method based on the tetramer models, we proposed a new aggregation mechanism of RRM domains in TDP-43, which could well characterize the formation of the large aggregation models with the repeated, helical and rope-like structures. These new insights help to understand the amyloid-like aggregation phenomena of TDP-43 protein in ALS and FTLD diseases.
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spelling pubmed-83713692021-08-26 Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration Liu, Wei Li, Chaoqun Shan, Jiankai Wang, Yan Chen, Guangju R Soc Open Sci Chemistry The transactive response DNA-binding protein 43 (TDP-43) is associated with several diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) due to pathogenic aggregations. In this work, we examined the dimer, tetramer and hexamer models built from the RRM domains of TDP-43 using molecular dynamics simulations in combination with the protein–protein docking. Our results showed that the formations of the dimer models are mainly achieved by the interactions of the RRM1 domains. The parallel β-sheet layers between the RRM1 domains provide most of the binding sites in these oligomer models, and thus play an important role in the aggregation process. The approaching of the parallel β-sheet layers from small oligomer models gradually expand to large ones through the allosteric communication between the α1/α2 helices of the RRM1 domains, which maintains the binding affinities and interactions in the larger oligomer models. Using the repeatable-superimposing method based on the tetramer models, we proposed a new aggregation mechanism of RRM domains in TDP-43, which could well characterize the formation of the large aggregation models with the repeated, helical and rope-like structures. These new insights help to understand the amyloid-like aggregation phenomena of TDP-43 protein in ALS and FTLD diseases. The Royal Society 2021-08-18 /pmc/articles/PMC8371369/ /pubmed/34457335 http://dx.doi.org/10.1098/rsos.210160 Text en © 2021 The Authors. https://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, provided the original author and source are credited.
spellingShingle Chemistry
Liu, Wei
Li, Chaoqun
Shan, Jiankai
Wang, Yan
Chen, Guangju
Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title_full Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title_fullStr Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title_full_unstemmed Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title_short Insights into the aggregation mechanism of RNA recognition motif domains in TDP-43: a theoretical exploration
title_sort insights into the aggregation mechanism of rna recognition motif domains in tdp-43: a theoretical exploration
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371369/
https://www.ncbi.nlm.nih.gov/pubmed/34457335
http://dx.doi.org/10.1098/rsos.210160
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