The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ
dc.contributor.author | Williams, Danielle M. | |
dc.contributor.author | Thorn, David C. | |
dc.contributor.author | Dobson, Christopher M. | |
dc.contributor.author | Meehan, Sarah | |
dc.contributor.author | Jackson, Sophie E. | |
dc.contributor.author | Woodcock, Joanna M. | |
dc.contributor.author | Carver, John A. | |
dc.contributor.orcid | Thorn, David C. [0000-0002-7332-2292] | |
dc.contributor.orcid | Meehan, Sarah [0000-0002-2778-4373] | |
dc.contributor.orcid | Woodcock, Joanna M. [0000-0001-5127-9687] | |
dc.contributor.orcid | Carver, John A. [0000-0002-2441-8108] | |
dc.date.accessioned | 2021-10-13T09:46:38Z | |
dc.date.available | 2021-10-13T09:46:38Z | |
dc.date.issued | 2021-10-11 | |
dc.date.updated | 2021-10-13T09:46:38Z | |
dc.description.abstract | 14-3-3 proteins are abundant, intramolecular proteins that play a pivotal role in cellular signal transduction by interacting with phosphorylated ligands. In addition, they are molecular chaperones that prevent protein unfolding and aggregation under cellular stress conditions in a similar manner to the unrelated small heat-shock proteins. In vivo, amyloid β (Aβ) and α-synuclein (α-syn) form amyloid fibrils in Alzheimer’s and Parkinson’s diseases, respectively, a process that is intimately linked to the diseases’ progression. The 14-3-3ζ isoform potently inhibited in vitro fibril formation of the 40-amino acid form of Aβ (Aβ40) but had little effect on α-syn aggregation. Solution-phase NMR spectroscopy of 15N-labeled Aβ40 and A53T α-syn determined that unlabeled 14-3-3ζ interacted preferentially with hydrophobic regions of Aβ40 (L11-H21 and G29-V40) and α-syn (V3-K10 and V40-K60). In both proteins, these regions adopt β-strands within the core of the amyloid fibrils prepared in vitro as well as those isolated from the inclusions of diseased individuals. The interaction with 14-3-3ζ is transient and occurs at the early stages of the fibrillar aggregation pathway to maintain the native, monomeric, and unfolded structure of Aβ40 and α-syn. The N-terminal regions of α-syn interacting with 14-3-3ζ correspond with those that interact with other molecular chaperones as monitored by in-cell NMR spectroscopy. | |
dc.identifier.doi | 10.17863/CAM.76769 | |
dc.identifier.eissn | 1420-3049 | |
dc.identifier.uri | https://www.repository.cam.ac.uk/handle/1810/329321 | |
dc.language | en | |
dc.publisher | MDPI | |
dc.subject | 14-3-3 proteins | |
dc.subject | molecular chaperone | |
dc.subject | amyloid β | |
dc.subject | α-synuclein | |
dc.subject | NMR spectroscopy | |
dc.subject | amyloid fibril | |
dc.title | The Amyloid Fibril-Forming β-Sheet Regions of Amyloid β and α-Synuclein Preferentially Interact with the Molecular Chaperone 14-3-3ζ | |
dc.type | Article | |
dcterms.dateAccepted | 2021-10-03 | |
prism.issueIdentifier | 20 | |
prism.publicationName | Molecules | |
prism.volume | 26 | |
pubs.funder-project-id | National Health and Medical Research Council (1068087) | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0/ | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.3390/molecules26206120 |
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