Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding
Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
Journal of biomolecular structure & dynamics - (2023) vom: 21. Dez., Seite 1-13 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Alamri, Sultan H [VerfasserIn] |
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| Links: |
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| Themen: |
α-Synuclein |
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| Anmerkungen: |
Date Revised 26.12.2023 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1080/07391102.2023.2293258 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366168460 |
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| 520 | |a Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.Communicated by Ramaswamy H. Sarma | ||
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| 700 | 1 | |a Alghamdi, Badra S |e verfasserin |4 aut | |
| 700 | 1 | |a Tayeb, Haythum O |e verfasserin |4 aut | |
| 700 | 1 | |a Azhari, Shereen |e verfasserin |4 aut | |
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| 700 | 1 | |a Alamri, Turki A |e verfasserin |4 aut | |
| 700 | 1 | |a Harakeh, Steve |e verfasserin |4 aut | |
| 700 | 1 | |a Prakash, Amresh |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Vijay |e verfasserin |4 aut | |
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