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Article

Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly

1
Department of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, Sweden
2
Department of Natural Sciences, School of Science and Technology, University of Georgia, 0171 Tbilisi, Georgia
3
Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
4
Department of Biotechnology, University of Rijeka, HR-51000 Rijeka, Croatia
*
Authors to whom correspondence should be addressed.
Academic Editor: Irina M. Kuznetsova
Int. J. Mol. Sci. 2021, 22(16), 8556; https://doi.org/10.3390/ijms22168556
Received: 28 June 2021 / Revised: 3 August 2021 / Accepted: 5 August 2021 / Published: 9 August 2021
(This article belongs to the Special Issue Amyloid Hetero-Aggregation)
The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases. View Full-Text
Keywords: amyloid; binding; cyclen; DOPA; morphology; S100A9 amyloid; binding; cyclen; DOPA; morphology; S100A9
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MDPI and ACS Style

Arabuli, L.; Iashchishyn, I.A.; Romanova, N.V.; Musteikyte, G.; Smirnovas, V.; Chaudhary, H.; Svedružić, Ž.M.; Morozova-Roche, L.A. Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly. Int. J. Mol. Sci. 2021, 22, 8556. https://doi.org/10.3390/ijms22168556

AMA Style

Arabuli L, Iashchishyn IA, Romanova NV, Musteikyte G, Smirnovas V, Chaudhary H, Svedružić ŽM, Morozova-Roche LA. Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly. International Journal of Molecular Sciences. 2021; 22(16):8556. https://doi.org/10.3390/ijms22168556

Chicago/Turabian Style

Arabuli, Lili, Igor A. Iashchishyn, Nina V. Romanova, Greta Musteikyte, Vytautas Smirnovas, Himanshu Chaudhary, Željko M. Svedružić, and Ludmilla A. Morozova-Roche. 2021. "Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly" International Journal of Molecular Sciences 22, no. 16: 8556. https://doi.org/10.3390/ijms22168556

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