Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly
Recent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and...
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doaj-004160071e684a15a2229bd83334350a2020-11-25T03:31:12ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-01215061506110.3390/ijms21145061Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid AssemblyOscar Palomino-Hernandez0Fiamma A. Buratti1Pamela S. Sacco2Giulia Rossetti3Paolo Carloni4Claudio O. Fernandez5Computational Biomedicine, Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5), Forschungszentrum Jülich, 52425 Jülich, GermanyMax Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Rosario S2002LRK, ArgentinaMax Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Rosario S2002LRK, ArgentinaComputational Biomedicine, Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5), Forschungszentrum Jülich, 52425 Jülich, GermanyComputational Biomedicine, Institute for Neuroscience and Medicine (INM-9) and Institute for Advanced Simulations (IAS-5), Forschungszentrum Jülich, 52425 Jülich, GermanyMax Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC) and Instituto de Investigaciones para el Descubrimiento de Fármacos de Rosario (IIDEFAR, UNR-CONICET), Universidad Nacional de Rosario, Rosario S2002LRK, ArgentinaRecent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and its Y39A, Y39F, and Y39L variants. By the combined application of site-directed mutagenesis, biophysical techniques, and enhanced sampling molecular simulations, we show that removing aromatic functionality at position 39 of monomeric αS leads to protein variants populating more compact conformations, conserving its disordered nature and secondary structure propensities. Contrasting with the subtle changes induced by mutations on the protein structure, removing aromaticity at position 39 impacts strongly on the interaction of αS with the potent amyloid inhibitor phthalocyanine tetrasulfonate (PcTS). Our findings further support the role of Tyr-39 in forming essential inter and intramolecular contacts that might have important repercussions for the function and the dysfunction of αS.https://www.mdpi.com/1422-0067/21/14/5061alpha synucleinmutagenesisaromaticityaggregationmolecular simulation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Oscar Palomino-Hernandez Fiamma A. Buratti Pamela S. Sacco Giulia Rossetti Paolo Carloni Claudio O. Fernandez |
spellingShingle |
Oscar Palomino-Hernandez Fiamma A. Buratti Pamela S. Sacco Giulia Rossetti Paolo Carloni Claudio O. Fernandez Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly International Journal of Molecular Sciences alpha synuclein mutagenesis aromaticity aggregation molecular simulation |
author_facet |
Oscar Palomino-Hernandez Fiamma A. Buratti Pamela S. Sacco Giulia Rossetti Paolo Carloni Claudio O. Fernandez |
author_sort |
Oscar Palomino-Hernandez |
title |
Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly |
title_short |
Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly |
title_full |
Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly |
title_fullStr |
Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly |
title_full_unstemmed |
Role of Tyr-39 for the Structural Features of α-Synuclein and for the Interaction with a Strong Modulator of Its Amyloid Assembly |
title_sort |
role of tyr-39 for the structural features of α-synuclein and for the interaction with a strong modulator of its amyloid assembly |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-07-01 |
description |
Recent studies suggest that Tyr-39 might play a critical role for both the normal function and the pathological dysfunction of α-synuclein (αS), an intrinsically disordered protein involved in Parkinson’s disease. We perform here a comparative analysis between the structural features of human αS and its Y39A, Y39F, and Y39L variants. By the combined application of site-directed mutagenesis, biophysical techniques, and enhanced sampling molecular simulations, we show that removing aromatic functionality at position 39 of monomeric αS leads to protein variants populating more compact conformations, conserving its disordered nature and secondary structure propensities. Contrasting with the subtle changes induced by mutations on the protein structure, removing aromaticity at position 39 impacts strongly on the interaction of αS with the potent amyloid inhibitor phthalocyanine tetrasulfonate (PcTS). Our findings further support the role of Tyr-39 in forming essential inter and intramolecular contacts that might have important repercussions for the function and the dysfunction of αS. |
topic |
alpha synuclein mutagenesis aromaticity aggregation molecular simulation |
url |
https://www.mdpi.com/1422-0067/21/14/5061 |
work_keys_str_mv |
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