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dc.contributor.authorLee, Ji-Eun
dc.contributor.authorSang, Chieh
dc.contributor.authorRodrigues, Margarida
dc.contributor.authorCarr, Alexander R
dc.contributor.authorHorrocks, Mathew
dc.contributor.authorDe, Suman
dc.contributor.authorBongiovanni, Marie N
dc.contributor.authorFlagmeier, Patrick
dc.contributor.authorDobson, Christopher
dc.contributor.authorWales, David
dc.contributor.authorLee, Steven
dc.contributor.authorKlenerman, David
dc.date.accessioned2018-12-11T00:30:19Z
dc.date.available2018-12-11T00:30:19Z
dc.date.issued2018-12-12
dc.identifier.issn1530-6984
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/286598
dc.description.abstractProteins fold into a single structural ensemble but can also misfold into many diverse structures including small aggregates and fibrils, which differ in their toxicity. The aggregate surface properties play an important role in how they interact with the plasma membrane and cellular organelles, potentially inducing cellular toxicity, however, these properties have not been measured to date due to the lack of suitable methods. Here, we used a spectrally resolved, super-resolution imaging method combined with an environmentally sensitive fluorescent dye to measure the surface hydrophobicity of individual aggregates formed by the protein α-synuclein (αS), whose aggregation is associated with Parkinson's disease. We show that the surface of soluble oligomers is more hydrophobic than fibrils and populates a diverse range of coexisting states. Overall, our data show that the conversion of oligomers to fibril-like aggregates and ultimately to fibrils results in a reduction in both hydrophobicity and the variation in hydrophobicity. This funneling characteristic of the energy landscape explains many of the observed properties of αS aggregates and may be a common feature of aggregating proteins.
dc.description.sponsorshipC.M.D. is supported by the Wellcome Trust (094425/Z/10/Z) and the UK Biotechnology and Biochemical Sciences Research Council (BB/H003843/1). D.J.W. is supported by the UK Engineering and Physical Science Research Council (EP/L504920/1). S.F.L. is supported by the Royal Society (UF120277). D.K. is a Royal Society Professor of Molecular Medicine and funded by the European Research Council (669237) and MRC (MR/K015850/1). We thank the members of the Klenerman and Lee research groups for their input and discussion, in particular we would like to thank Dr. Juan Varela, Dr. Aleks Ponjavic, Dr. Marija Iljina, and Dr. Alex Herbert for their helpful discussion.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHumans
dc.subjectParkinson Disease
dc.subjectFluorescent Dyes
dc.subjectSolubility
dc.subjectalpha-Synuclein
dc.subjectProtein Multimerization
dc.subjectHydrophobic and Hydrophilic Interactions
dc.subjectOptical Imaging
dc.subjectProtein Aggregates
dc.subjectProtein Aggregation, Pathological
dc.titleMapping Surface Hydrophobicity of α-Synuclein Oligomers at the Nanoscale.
dc.typeArticle
prism.endingPage7501
prism.issueIdentifier12
prism.publicationDate2018
prism.publicationNameNano Lett
prism.startingPage7494
prism.volume18
dc.identifier.doi10.17863/CAM.33910
dcterms.dateAccepted2018-10-31
rioxxterms.versionofrecord10.1021/acs.nanolett.8b02916
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-12
dc.contributor.orcidLee, Ji-Eun [0000-0001-5954-2638]
dc.contributor.orcidSang, Chieh [0000-0002-8567-5415]
dc.contributor.orcidDe, Suman [0000-0003-1675-0773]
dc.contributor.orcidFlagmeier, Patrick [0000-0002-1204-5340]
dc.contributor.orcidWales, David [0000-0002-3555-6645]
dc.contributor.orcidLee, Steven [0000-0003-4492-5139]
dc.contributor.orcidKlenerman, David [0000-0001-7116-6954]
dc.identifier.eissn1530-6992
rioxxterms.typeJournal Article/Review
pubs.funder-project-idEuropean Research Council (669237)
pubs.funder-project-idWellcome Trust (094425/Z/10/Z)
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/H003843/1)
pubs.funder-project-idMedical Research Council (MR/K015850/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/L504920/1)
pubs.funder-project-idEngineering and Physical Sciences Research Council (EP/N035003/1)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (701013)
cam.issuedOnline2018-10-31


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International