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Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein
α-Synuclein (140 amino acids), one of the causative proteins of Parkinson's disease, forms amyloid fibrils in brain neuronal cells. In order to further explore the contributions of the C-terminal region of α-synuclein in fibril formation and also to understand the overall mechanism of fibril fo...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Inc
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489812/ https://www.ncbi.nlm.nih.gov/pubmed/23139905 http://dx.doi.org/10.1002/brb3.86 |
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author | Izawa, Yasutaka Tateno, Hironobu Kameda, Hiroshi Hirakawa, Kazuya Hato, Keiko Yagi, Hisashi Hongo, Kunihiro Mizobata, Tomohiro Kawata, Yasushi |
author_facet | Izawa, Yasutaka Tateno, Hironobu Kameda, Hiroshi Hirakawa, Kazuya Hato, Keiko Yagi, Hisashi Hongo, Kunihiro Mizobata, Tomohiro Kawata, Yasushi |
author_sort | Izawa, Yasutaka |
collection | PubMed |
description | α-Synuclein (140 amino acids), one of the causative proteins of Parkinson's disease, forms amyloid fibrils in brain neuronal cells. In order to further explore the contributions of the C-terminal region of α-synuclein in fibril formation and also to understand the overall mechanism of fibril formation, we reduced the number of negatively charged residues in the C-terminal region using mutagenesis. Mutants with negative charges deleted displayed accelerated fibril formation compared with wild-type α-synuclein, demonstrating that negative charges located in the C-terminal region of α-synuclein modulate fibril formation. Additionally, when tyrosine residues located at position 125, 133, and 136 in the C-terminal region were changed to alanine residue(s), we found that all mutants containing the Tyr136Ala mutation showed delays in fibril formation compared with wild type. Mutation of Tyr136 to various amino acids revealed that aromatic residues located at this position act favorably toward fibril formation. In mutants where charge neutralization and tyrosine substitution were combined, we found that these two factors influence fibril formation in complex fashion. These findings highlight the importance of negative charges and aromatic side chains in the C-terminal region of α-synuclein in fibril formation. |
format | Online Article Text |
id | pubmed-3489812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Inc |
record_format | MEDLINE/PubMed |
spelling | pubmed-34898122012-11-08 Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein Izawa, Yasutaka Tateno, Hironobu Kameda, Hiroshi Hirakawa, Kazuya Hato, Keiko Yagi, Hisashi Hongo, Kunihiro Mizobata, Tomohiro Kawata, Yasushi Brain Behav Original Research α-Synuclein (140 amino acids), one of the causative proteins of Parkinson's disease, forms amyloid fibrils in brain neuronal cells. In order to further explore the contributions of the C-terminal region of α-synuclein in fibril formation and also to understand the overall mechanism of fibril formation, we reduced the number of negatively charged residues in the C-terminal region using mutagenesis. Mutants with negative charges deleted displayed accelerated fibril formation compared with wild-type α-synuclein, demonstrating that negative charges located in the C-terminal region of α-synuclein modulate fibril formation. Additionally, when tyrosine residues located at position 125, 133, and 136 in the C-terminal region were changed to alanine residue(s), we found that all mutants containing the Tyr136Ala mutation showed delays in fibril formation compared with wild type. Mutation of Tyr136 to various amino acids revealed that aromatic residues located at this position act favorably toward fibril formation. In mutants where charge neutralization and tyrosine substitution were combined, we found that these two factors influence fibril formation in complex fashion. These findings highlight the importance of negative charges and aromatic side chains in the C-terminal region of α-synuclein in fibril formation. Blackwell Publishing Inc 2012-09 2012-08-10 /pmc/articles/PMC3489812/ /pubmed/23139905 http://dx.doi.org/10.1002/brb3.86 Text en Copyright © 2012 Wiley Periodicals, Inc. http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. |
spellingShingle | Original Research Izawa, Yasutaka Tateno, Hironobu Kameda, Hiroshi Hirakawa, Kazuya Hato, Keiko Yagi, Hisashi Hongo, Kunihiro Mizobata, Tomohiro Kawata, Yasushi Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title | Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title_full | Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title_fullStr | Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title_full_unstemmed | Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title_short | Role of C-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
title_sort | role of c-terminal negative charges and tyrosine residues in fibril formation of α-synuclein |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3489812/ https://www.ncbi.nlm.nih.gov/pubmed/23139905 http://dx.doi.org/10.1002/brb3.86 |
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