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Open AccessArticle

The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin

1
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
2
Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaløes vej 5, 2200 Copenhagen N, Denmark
3
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Italy
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(8), 1192; https://doi.org/10.3390/biom10081192
Received: 20 July 2020 / Revised: 12 August 2020 / Accepted: 14 August 2020 / Published: 16 August 2020
The intrinsically disordered protein α-synuclein (aSN) is, in its fibrillated state, the main component of Lewy bodies—hallmarks of Parkinson’s disease. Additional Lewy body components include glycosaminoglycans, including heparan sulfate proteoglycans. In humans, heparan sulfate has, in an age-dependent manner, shown increased levels of sulfation. Heparin, a highly sulfated glycosaminoglycan, is a relevant mimic for mature heparan sulfate and has been shown to influence aSN fibrillation. Here, we decompose the underlying properties of the interaction between heparin and aSN and the effect of heparin on fibrillation. Via the isolation of the first 61 residues of aSN, which lacked intrinsic fibrillation propensity, fibrillation could be induced by heparin, and access to the initial steps in fibrillation was possible. Here, structural changes with shifts from disorder via type I β-turns to β-sheets were revealed, correlating with an increase in the aSN1–61/heparin molar ratio. Fluorescence microscopy revealed that heparin and aSN1–61 co-exist in the final fibrils. We conclude that heparin can induce the fibrillation of aSN1–61, through binding to the N-terminal with an affinity that is higher in the truncated form of aSN. It does so by specifically modulating the structure of aSN via the formation of type I β-turn structures likely critical for triggering aSN fibrillation. View Full-Text
Keywords: α-synuclein; heparin; fibrillation; NMR; binding; IDP; intrinsically disordered proteins; SAXS; Parkinson’s disease; type I β-turn α-synuclein; heparin; fibrillation; NMR; binding; IDP; intrinsically disordered proteins; SAXS; Parkinson’s disease; type I β-turn
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Skaanning, L.K.; Santoro, A.; Skamris, T.; Martinsen, J.H.; D’Ursi, A.M.; Bucciarelli, S.; Vestergaard, B.; Bugge, K.; Langkilde, A.E.; Kragelund, B.B. The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin. Biomolecules 2020, 10, 1192.

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