DOI: 10.1073/pnas.0902603106. Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation

Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation

10.1073/pnas.0902603106

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The identification of aggregation inhibitors and the investigation of their mechanism of action are fundamental in the quest to mitigate the pathological consequences of amyloid formation. Here, characterization of the structural and mechanistic basis for the antiamyloidogenic effect of phthalocyanine tetrasulfonate (PcTS) on α-synuclein (AS) allowed us to demonstrate that specific aromatic interactions are central for ligand-mediated inhibition of amyloid formation. We provide evidence indicating that the mechanism behind the antiamyloidogenic effect of PcTS is correlated with the trapping of prefibrillar AS species during the early stages of the assembly process. By using NMR spectroscopy, we have located the primary binding region for PcTS to a specific site in the N terminus of AS, involving the amino acid Tyr-39 as the anchoring residue. Moreover, the residue-specific structural characterization of the AS-PcTS complex provided the basis for the rational design of nonamyloidogenic species of AS, highlighting the role of aromatic interactions in driving AS amyloid assembly. A comparative analysis with other proteins involved in neurodegenerative disorders reveals that aromatic recognition interfaces might constitute a key structural element to target their aggregation pathways. These findings emphasize the use of aggregation inhibitors as molecular probes to assess structural and toxic mechanisms related to amyloid formation and the potential of small molecules as therapeutics for amyloid-related pathologies.

Bibliography

Lamberto, G. R., Binolfi, A., Orcellet, M. L., Bertoncini, C. W., Zweckstetter, M., Griesinger, C., & FernÃ¡ndez, C. O. (2009). Structural and mechanistic basis behind the inhibitory interaction of PcTS on Î±-synuclein amyloid fibril formation. Proceedings of the National Academy of Sciences, 106(50), 21057â21062.

Authors 7

Gonzalo R. Lamberto (first)
Andrés Binolfi (additional)
María L. Orcellet (additional)
Carlos W. Bertoncini (additional)
Markus Zweckstetter (additional)
Christian Griesinger (additional)
Claudio O. Fernández (additional)

References 37 Referenced 96

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Dates

Type	When
Created	15 years, 8 months ago (Nov. 30, 2009, 10:19 p.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 6:05 p.m.)
Indexed	1 week, 2 days ago (Aug. 21, 2025, 1:05 p.m.)
Issued	15 years, 8 months ago (Dec. 15, 2009)
Published	15 years, 8 months ago (Dec. 15, 2009)
Published Online	15 years, 8 months ago (Dec. 15, 2009)
Published Print	15 years, 8 months ago (Dec. 15, 2009)

Funders 0

None

BibTeX

@article{Lamberto_2009, title={Structural and mechanistic basis behind the inhibitory interaction of PcTS on α-synuclein amyloid fibril formation}, volume={106}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0902603106}, DOI={10.1073/pnas.0902603106}, number={50}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Lamberto, Gonzalo R. and Binolfi, Andrés and Orcellet, María L. and Bertoncini, Carlos W. and Zweckstetter, Markus and Griesinger, Christian and Fernández, Claudio O.}, year={2009}, month=dec, pages={21057–21062} }

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