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RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles
RepA-WH1 is a disease-unrelated protein that recapitulates in bacteria key aspects of human amyloid proteinopathies: i) It undergoes ligand-promoted amyloidogenesis in vitro; ii) its aggregates are able to seed/template amyloidosis on soluble protein molecules; iii) its conformation is modulated by...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794723/ https://www.ncbi.nlm.nih.gov/pubmed/26984374 http://dx.doi.org/10.1038/srep23144 |
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author | Fernández, Cristina Núñez-Ramírez, Rafael Jiménez, Mercedes Rivas, Germán Giraldo, Rafael |
author_facet | Fernández, Cristina Núñez-Ramírez, Rafael Jiménez, Mercedes Rivas, Germán Giraldo, Rafael |
author_sort | Fernández, Cristina |
collection | PubMed |
description | RepA-WH1 is a disease-unrelated protein that recapitulates in bacteria key aspects of human amyloid proteinopathies: i) It undergoes ligand-promoted amyloidogenesis in vitro; ii) its aggregates are able to seed/template amyloidosis on soluble protein molecules; iii) its conformation is modulated by Hsp70 chaperones in vivo, generating transmissible amyloid strains; and iv) causes proliferative senescence. Membrane disruption by amyloidogenic oligomers has been found for most proteins causing human neurodegenerative diseases. Here we report that, as for PrP prion and α-synuclein, acidic phospholipids also promote RepA-WH1 amyloidogenesis in vitro. RepA-WH1 molecules bind to liposomes, where the protein assembles oligomeric membrane pores. Fluorescent tracer molecules entrapped in the lumen of the vesicles leak through these pores and RepA-WH1 can then form large aggregates on the surface of the vesicles without inducing their lysis. These findings prove that it is feasible to generate in vitro a synthetic proteinopathy with a minimal set of cytomimetic components and support the view that cell membranes are primary targets in protein amyloidoses. |
format | Online Article Text |
id | pubmed-4794723 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47947232016-03-18 RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles Fernández, Cristina Núñez-Ramírez, Rafael Jiménez, Mercedes Rivas, Germán Giraldo, Rafael Sci Rep Article RepA-WH1 is a disease-unrelated protein that recapitulates in bacteria key aspects of human amyloid proteinopathies: i) It undergoes ligand-promoted amyloidogenesis in vitro; ii) its aggregates are able to seed/template amyloidosis on soluble protein molecules; iii) its conformation is modulated by Hsp70 chaperones in vivo, generating transmissible amyloid strains; and iv) causes proliferative senescence. Membrane disruption by amyloidogenic oligomers has been found for most proteins causing human neurodegenerative diseases. Here we report that, as for PrP prion and α-synuclein, acidic phospholipids also promote RepA-WH1 amyloidogenesis in vitro. RepA-WH1 molecules bind to liposomes, where the protein assembles oligomeric membrane pores. Fluorescent tracer molecules entrapped in the lumen of the vesicles leak through these pores and RepA-WH1 can then form large aggregates on the surface of the vesicles without inducing their lysis. These findings prove that it is feasible to generate in vitro a synthetic proteinopathy with a minimal set of cytomimetic components and support the view that cell membranes are primary targets in protein amyloidoses. Nature Publishing Group 2016-03-17 /pmc/articles/PMC4794723/ /pubmed/26984374 http://dx.doi.org/10.1038/srep23144 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Fernández, Cristina Núñez-Ramírez, Rafael Jiménez, Mercedes Rivas, Germán Giraldo, Rafael RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title | RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title_full | RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title_fullStr | RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title_full_unstemmed | RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title_short | RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
title_sort | repa-wh1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794723/ https://www.ncbi.nlm.nih.gov/pubmed/26984374 http://dx.doi.org/10.1038/srep23144 |
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