Cargando…

Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence

Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body inclusions of patients with Parkinson’s disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylat...

Descripción completa

Detalles Bibliográficos
Autores principales: Kang, Lijuan, Janowska, Maria K., Moriarty, Gina M., Baum, Jean
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776725/
https://www.ncbi.nlm.nih.gov/pubmed/24058647
http://dx.doi.org/10.1371/journal.pone.0075018
_version_ 1782477515334352896
author Kang, Lijuan
Janowska, Maria K.
Moriarty, Gina M.
Baum, Jean
author_facet Kang, Lijuan
Janowska, Maria K.
Moriarty, Gina M.
Baum, Jean
author_sort Kang, Lijuan
collection PubMed
description Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body inclusions of patients with Parkinson’s disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylation on fibrillation by first establishing a quantitative relationship between monomer secondary structural propensity and fibril assembly kinetics, and secondly by demonstrating in the N-terminal acetylated form of the early onset A53T mutation, that N-terminal transient helices formed and/or inhibited by N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical shifts and fluorescence experiments, we report that secondary structural propensity in residues 5–8, 14–31, and 50–57 are highly correlated to fibril growth rate. A four-way comparison of secondary structure propensity and fibril growth rates of N-terminally acetylated A53T and WT αSyn with non-acetylated A53T and WT αSyn present novel mechanistic insight into the role of N-terminal acetylation in amyloid fibril formation. We show that N-terminal acetylation inhibits the formation of the “fibrillation promoting” transient helix at residues 14–31 resulting from the A53T mutation in the non-acetylated variant and supports the formation of the “fibrillation inhibiting” transient helix in residues 1–12 thereby resulting in slower fibrillation rates relative to the previously studied non-acetylated A53T variant. Our results highlight the critical interplay of the region-specific transient secondary structure of the N-terminal region with fibrillation, and the inhibitory role of the N-terminal acetyl group in fibril formation.
format Online
Article
Text
id pubmed-3776725
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37767252013-09-20 Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence Kang, Lijuan Janowska, Maria K. Moriarty, Gina M. Baum, Jean PLoS One Research Article Aggregation of α-synuclein (αSyn), the primary protein component in Lewy body inclusions of patients with Parkinson’s disease, arises when the normally soluble intrinsically disordered protein converts to amyloid fibrils. In this work, we provide a mechanistic view of the role of N-terminal acetylation on fibrillation by first establishing a quantitative relationship between monomer secondary structural propensity and fibril assembly kinetics, and secondly by demonstrating in the N-terminal acetylated form of the early onset A53T mutation, that N-terminal transient helices formed and/or inhibited by N-terminal acetylation modulate the fibril assembly rates. Using NMR chemical shifts and fluorescence experiments, we report that secondary structural propensity in residues 5–8, 14–31, and 50–57 are highly correlated to fibril growth rate. A four-way comparison of secondary structure propensity and fibril growth rates of N-terminally acetylated A53T and WT αSyn with non-acetylated A53T and WT αSyn present novel mechanistic insight into the role of N-terminal acetylation in amyloid fibril formation. We show that N-terminal acetylation inhibits the formation of the “fibrillation promoting” transient helix at residues 14–31 resulting from the A53T mutation in the non-acetylated variant and supports the formation of the “fibrillation inhibiting” transient helix in residues 1–12 thereby resulting in slower fibrillation rates relative to the previously studied non-acetylated A53T variant. Our results highlight the critical interplay of the region-specific transient secondary structure of the N-terminal region with fibrillation, and the inhibitory role of the N-terminal acetyl group in fibril formation. Public Library of Science 2013-09-18 /pmc/articles/PMC3776725/ /pubmed/24058647 http://dx.doi.org/10.1371/journal.pone.0075018 Text en © 2013 Kang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Kang, Lijuan
Janowska, Maria K.
Moriarty, Gina M.
Baum, Jean
Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title_full Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title_fullStr Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title_full_unstemmed Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title_short Mechanistic Insight into the Relationship between N-Terminal Acetylation of α-Synuclein and Fibril Formation Rates by NMR and Fluorescence
title_sort mechanistic insight into the relationship between n-terminal acetylation of α-synuclein and fibril formation rates by nmr and fluorescence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776725/
https://www.ncbi.nlm.nih.gov/pubmed/24058647
http://dx.doi.org/10.1371/journal.pone.0075018
work_keys_str_mv AT kanglijuan mechanisticinsightintotherelationshipbetweennterminalacetylationofasynucleinandfibrilformationratesbynmrandfluorescence
AT janowskamariak mechanisticinsightintotherelationshipbetweennterminalacetylationofasynucleinandfibrilformationratesbynmrandfluorescence
AT moriartyginam mechanisticinsightintotherelationshipbetweennterminalacetylationofasynucleinandfibrilformationratesbynmrandfluorescence
AT baumjean mechanisticinsightintotherelationshipbetweennterminalacetylationofasynucleinandfibrilformationratesbynmrandfluorescence