Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase
The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediat...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12983 |
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| author | Aitor Franco Jorge Cuéllar José Ángel Fernández-Higuero Igor de la Arada Natalia Orozco José M. Valpuesta Adelina Prado Arturo Muga |
| author_facet | Aitor Franco Jorge Cuéllar José Ángel Fernández-Higuero Igor de la Arada Natalia Orozco José M. Valpuesta Adelina Prado Arturo Muga |
| author_sort | Aitor Franco |
| collection | DOAJ |
| description | The aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo. |
| first_indexed | 2024-03-10T04:52:10Z |
| format | Article |
| id | doaj.art-4aee3d07d70c4626ba48ad2d0283857c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:52:10Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-4aee3d07d70c4626ba48ad2d0283857c2023-11-23T02:31:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231298310.3390/ijms222312983Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based DisaggregaseAitor Franco0Jorge Cuéllar1José Ángel Fernández-Higuero2Igor de la Arada3Natalia Orozco4José M. Valpuesta5Adelina Prado6Arturo Muga7Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, SpainDepartment of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, SpainInstituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, 48940 Leioa, SpainInstituto Biofisika (UPV/EHU, CSIC), University of the Basque Country, 48940 Leioa, SpainDepartment of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, SpainDepartment of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), 48080 Bilbao, SpainThe aggregation of α-synuclein is the hallmark of a collective of neurodegenerative disorders known as synucleinopathies. The tendency to aggregate of this protein, the toxicity of its aggregation intermediates and the ability of the cellular protein quality control system to clear these intermediates seems to be regulated, among other factors, by post-translational modifications (PTMs). Among these modifications, we consider herein proteolysis at both the N- and C-terminal regions of α-synuclein as a factor that could modulate disassembly of toxic amyloids by the human disaggregase, a combination of the chaperones Hsc70, DnaJB1 and Apg2. We find that, in contrast to aggregates of the protein lacking the N-terminus, which can be solubilized as efficiently as those of the WT protein, the deletion of the C-terminal domain, either in a recombinant context or as a consequence of calpain treatment, impaired Hsc70-mediated amyloid disassembly. Progressive removal of the negative charges at the C-terminal region induces lateral association of fibrils and type B* oligomers, precluding chaperone action. We propose that truncation-driven aggregate clumping impairs the mechanical action of chaperones, which includes fast protofilament unzipping coupled to depolymerization. Inhibition of the chaperone-mediated clearance of C-truncated species could explain their exacerbated toxicity and higher propensity to deposit found in vivo.https://www.mdpi.com/1422-0067/22/23/12983α-synucleinamyloid disassemblysuprafibrillar assemblieschaperonehuman disaggregaseHsp70 |
| spellingShingle | Aitor Franco Jorge Cuéllar José Ángel Fernández-Higuero Igor de la Arada Natalia Orozco José M. Valpuesta Adelina Prado Arturo Muga Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase International Journal of Molecular Sciences α-synuclein amyloid disassembly suprafibrillar assemblies chaperone human disaggregase Hsp70 |
| title | Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase |
| title_full | Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase |
| title_fullStr | Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase |
| title_full_unstemmed | Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase |
| title_short | Truncation-Driven Lateral Association of α-Synuclein Hinders Amyloid Clearance by the Hsp70-Based Disaggregase |
| title_sort | truncation driven lateral association of α synuclein hinders amyloid clearance by the hsp70 based disaggregase |
| topic | α-synuclein amyloid disassembly suprafibrillar assemblies chaperone human disaggregase Hsp70 |
| url | https://www.mdpi.com/1422-0067/22/23/12983 |
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