Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly
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 modif...
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doaj-b08e5f3d958f43319d74f8a0b7a4b88a2021-08-26T13:51:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-08-01228556855610.3390/ijms22168556Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-AssemblyLili Arabuli0Igor A. Iashchishyn1Nina V. Romanova2Greta Musteikyte3Vytautas Smirnovas4Himanshu Chaudhary5Željko M. Svedružić6Ludmilla A. Morozova-Roche7Department of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, SwedenDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, SwedenDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, SwedenInstitute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, LithuaniaInstitute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, LithuaniaDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, SwedenDepartment of Biotechnology, University of Rijeka, HR-51000 Rijeka, CroatiaDepartment of Medical Biochemistry and Biophysics, Umeå University, SE-90781 Umeå, SwedenThe 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 K<sub>d</sub> 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.https://www.mdpi.com/1422-0067/22/16/8556amyloidbindingcyclenDOPAmorphologyS100A9 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Lili Arabuli Igor A. Iashchishyn Nina V. Romanova Greta Musteikyte Vytautas Smirnovas Himanshu Chaudhary Željko M. Svedružić Ludmilla A. Morozova-Roche |
spellingShingle |
Lili Arabuli Igor A. Iashchishyn Nina V. Romanova Greta Musteikyte Vytautas Smirnovas Himanshu Chaudhary Željko M. Svedružić Ludmilla A. Morozova-Roche 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 amyloid binding cyclen DOPA morphology S100A9 |
author_facet |
Lili Arabuli Igor A. Iashchishyn Nina V. Romanova Greta Musteikyte Vytautas Smirnovas Himanshu Chaudhary Željko M. Svedružić Ludmilla A. Morozova-Roche |
author_sort |
Lili Arabuli |
title |
Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly |
title_short |
Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly |
title_full |
Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly |
title_fullStr |
Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly |
title_full_unstemmed |
Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly |
title_sort |
co-aggregation of s100a9 with dopa and cyclen-based compounds manifested in amyloid fibril thickening without altering rates of self-assembly |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-08-01 |
description |
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 K<sub>d</sub> 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. |
topic |
amyloid binding cyclen DOPA morphology S100A9 |
url |
https://www.mdpi.com/1422-0067/22/16/8556 |
work_keys_str_mv |
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