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Dissecting the effect of ALS mutation S375G on the conformational properties and aggregation dynamics of TDP-43 370-375 fragment.
- Source :
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Biophysical chemistry [Biophys Chem] 2024 Jul; Vol. 310, pp. 107230. Date of Electronic Publication: 2024 Mar 29. - Publication Year :
- 2024
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Abstract
- The aggregation of transactive response deoxyribonucleic acid (DNA) binding protein of 43 kDa (TDP-43) into ubiquitin-positive inclusions is closely associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and chronic traumatic encephalopathy. The 370-375 fragment of TDP-43 ( <superscript>370</superscript> GNNSYS <superscript>375</superscript> , TDP-43 <subscript>370-375</subscript> ), the amyloidogenic hexapeptides, can be prone to forming pathogenic amyloid fibrils with the characteristic of steric zippers. Previous experiments reported the ALS-associated mutation, serine 375 substituted by glycine (S375G) is linked to early onset disease and protein aggregation of TDP-43. Based on this, it is necessary to explore the underlying molecular mechanisms. By utilizing all-atom molecular dynamics (MD) simulations of 102 μs in total, we investigated the impact of S375G mutation on the conformational ensembles and oligomerization dynamics of TDP-43 <subscript>370-375</subscript> peptides. Our replica exchange MD simulations show that S375G mutation could promote the unstructured conformation formation and induce peptides to form a loose packed oligomer, thus inhibiting the aggregation of TDP-43 <subscript>370-375</subscript> . Further analyses suggest that S375G mutation displays a reduction effect on the number of total hydrogen bonds and contacts among TDP-43 <subscript>370-375</subscript> peptides. Hydrogen bonding and polar interactions among TDP-43 <subscript>370-375</subscript> peptides, as well as Y374-Y374 π-π stacking interaction, are attenuated by S375G mutation. Additional microsecond MD simulations demonstrate that S375G mutation could prohibit the conformational conversion to β-structure-rich aggregates and possess an inhibitory effect on the oligomerization dynamics of TDP-43 <subscript>370-375</subscript> . This study offers for the first time of molecular insights into the S375G mutation affecting the aggregation of TDP-43 <subscript>370-375</subscript> at the atomic level, and may open new avenues in the development of future site-specific mutation therapeutics.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Humans
Protein Conformation
Protein Aggregates
Peptide Fragments chemistry
Peptide Fragments genetics
Peptide Fragments metabolism
Molecular Dynamics Simulation
Amyotrophic Lateral Sclerosis genetics
Amyotrophic Lateral Sclerosis metabolism
DNA-Binding Proteins chemistry
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4200
- Volume :
- 310
- Database :
- MEDLINE
- Journal :
- Biophysical chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38615537
- Full Text :
- https://doi.org/10.1016/j.bpc.2024.107230