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Biomolecules
Volume 10
Issue 8
10.3390/biom10081192
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Article

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

by
Line K. Skaanning
1,
Angelo Santoro
2,3,
Thomas Skamris
1,
Jacob Hertz Martinsen
1,2,
Anna Maria D’Ursi
3,
Saskia Bucciarelli
1,
Bente Vestergaard
1,
Katrine Bugge
2,
Annette Eva Langkilde
1,* and
Birthe B. Kragelund
2,*
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
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Abstract

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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

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MDPI and ACS Style

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. https://doi.org/10.3390/biom10081192

AMA Style

Skaanning LK, Santoro A, Skamris T, Martinsen JH, D’Ursi AM, Bucciarelli S, Vestergaard B, Bugge K, Langkilde AE, Kragelund BB. The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin. Biomolecules. 2020; 10(8):1192. https://doi.org/10.3390/biom10081192

Chicago/Turabian Style

Skaanning, Line K., Angelo Santoro, Thomas Skamris, Jacob H. Martinsen, Anna M. D’Ursi, Saskia Bucciarelli, Bente Vestergaard, Katrine Bugge, Annette E. Langkilde, and Birthe B. Kragelund. 2020. "The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin" Biomolecules 10, no. 8: 1192. https://doi.org/10.3390/biom10081192

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