The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin
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The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin. / Skaanning, Line K.; Santoro, Angelo; Skamris, Thomas; Martinsen, Jacob Hertz; D’Ursi, Anna Maria; Bucciarelli, Saskia; Vestergaard, Bente; Bugge, Katrine; Langkilde, Annette Eva; Kragelund, Birthe B.
In: Biomolecules, Vol. 10, No. 8, 1192, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin
AU - Skaanning, Line K.
AU - Santoro, Angelo
AU - Skamris, Thomas
AU - Martinsen, Jacob Hertz
AU - D’Ursi, Anna Maria
AU - Bucciarelli, Saskia
AU - Vestergaard, Bente
AU - Bugge, Katrine
AU - Langkilde, Annette Eva
AU - Kragelund, Birthe B.
PY - 2020
Y1 - 2020
N2 - 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
AB - 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
U2 - 10.3390/biom10081192
DO - 10.3390/biom10081192
M3 - Journal article
C2 - 32824376
VL - 10
JO - Biomolecules
JF - Biomolecules
SN - 2218-273X
IS - 8
M1 - 1192
ER -
ID: 247211976