The extent of protein hydration dictates the preference for heterogeneous or homogeneous nucleation generating either parallel or antiparallel ß-sheet a-synuclein aggregates
Camino, J.D. (Universidad de Zaragoza) ; Gracia, P. ; Chen, S.W. ; Sot, J. ; De La Arada, I. ; Sebastián, V. (Universidad de Zaragoza) ; Arrondo, J.L.R. ; Goñi, F.M. ; Dobson, C.M. ; Cremades, N. (Universidad de Zaragoza)
Resumen: a-Synuclein amyloid self-assembly is the hallmark of a number of neurodegenerative disorders, including Parkinson 's disease, although there is still very limited understanding about the factors and mechanisms that trigger this process. Primary nucleation has been observed to be initiated in vitro at hydrophobic/hydrophilic interfaces by heterogeneous nucleation generating parallel ß-sheet aggregates, although no such interfaces have yet been identified in vivo. In this work, we have discovered that a-synuclein can self-assemble into amyloid aggregates by homogeneous nucleation, without the need of an active surface, and with a preference for an antiparallel ß-sheet arrangement. This particular structure has been previously proposed to be distinctive of stable toxic oligomers and we here demonstrate that it indeed represents the most stable structure of the preferred amyloid pathway triggered by homogeneous nucleation under limited hydration conditions, including those encountered inside a-synuclein droplets generated by liquid-liquid phase separation. In addition, our results highlight the key role that water plays not only in modulating the transition free energy of amyloid nucleation, and thus governing the initiation of the process, but also in dictating the type of preferred primary nucleation and the type of amyloid polymorph generated depending on the extent of protein hydration. These findings are particularly relevant in the context of in vivo a-synuclein aggregation where the protein can encounter a variety of hydration conditions in different cellular microenvironments, including the vicinity of lipid membranes or the interior of membraneless compartments, which could lead to the formation of remarkably different amyloid polymorphs by either heterogeneous or homogeneous nucleation.
Idioma: Inglés
DOI: 10.1039/d0sc05297c
Año: 2020
Publicado en: Chemical Science 11, 43 (2020), 11902-11914
ISSN: 2041-6520
Factor impacto JCR: 9.825 (2020)
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 22 / 178 = 0.124 (2020) - Q1 - T1
Factor impacto SCIMAGO: 3.686 - Chemistry (miscellaneous) (Q1)
Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100
Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/RTI2018-099019-A-I00
Financiación: info:eu-repo/grantAgreement/ES/MINECO-FEDER/BFU2015-64119-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068
Tipo y forma: Article (Published version)
Área (Departamento): Área Ingeniería Química (Dpto. Ing.Quím.Tecnol.Med.Amb.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes.
Exportado de SIDERAL (2021-09-02-10:30:01)
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Idioma: Inglés
DOI: 10.1039/d0sc05297c
Año: 2020
Publicado en: Chemical Science 11, 43 (2020), 11902-11914
ISSN: 2041-6520
Factor impacto JCR: 9.825 (2020)
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 22 / 178 = 0.124 (2020) - Q1 - T1
Factor impacto SCIMAGO: 3.686 - Chemistry (miscellaneous) (Q1)
Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/PGC2018-096335-B-100
Financiación: info:eu-repo/grantAgreement/ES/MCIU-FEDER/RTI2018-099019-A-I00
Financiación: info:eu-repo/grantAgreement/ES/MINECO-FEDER/BFU2015-64119-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/RYC-2012-12068
Tipo y forma: Article (Published version)
Área (Departamento): Área Ingeniería Química (Dpto. Ing.Quím.Tecnol.Med.Amb.)
Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)
You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not use the material for commercial purposes. Exportado de SIDERAL (2021-09-02-10:30:01)
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Articles > Artículos por área > Bioquímica y Biología Molecular
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Record created 2020-12-16, last modified 2021-09-02