Molecular Role of Ca2+ and Hard Divalent Metal Cations on Accelerated Fibrillation and Interfibrillar Aggregation of α-Synuclein

Jong Yoon Han, Tae Su Choi, Hugh I. Kim

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    47 Citations (Scopus)

    Abstract

    α-Synuclein (αSyn) is an intrinsically disordered protein, the aggregation of which is highly related to the pathology of diverse α-synucleinopathies. Various hard divalent metal cations have been shown to affect αSyn aggregation. Especially, Ca2+ is suggested to be a crucial ion due to its physiological relevance to α-synucleinopathies. However, the molecular origin of αSyn aggregation mediated by the metal ions is not fully elucidated. In this study, we revealed that hard divalent metal ions had almost identical influences on αSyn aggregation. Based on these similarities, the molecular role of Ca2+ was investigated as a representative metal ion. Herein, we demonstrated that binding of multiple Ca2+ ions induces structural transition of αSyn monomers to extended conformations, which promotes rapid αSyn fibrillation. Additionally, we observed that Ca2+ induced further interfibrillar aggregation via electrostatic and hydrophobic interactions. Our results from multiple biophysical methods, including ion mobility-mass spectrometry (IM-MS), synchrotron small-angle X-ray scattering (SAXS), transmission electron microscopy (TEM), provide detailed information on the structural change of αSyn and the aggregation process mediated by Ca2+. Overall, our study would be valuable for understanding the influence of Ca2+ on the aggregation of αSyn during the pathogenesis of α-synucleinopathies.

    Original languageEnglish
    Article number1895
    JournalScientific reports
    Volume8
    Issue number1
    DOIs
    Publication statusPublished - 2018 Dec 1

    Bibliographical note

    Funding Information:
    This work was supported by a Basic Research Program (Grant No. NRF-2016R1A2B4013089 and 20100020209) through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science, ICT, and Future Planning (MSIP), the National Research Council of Science & Technology (NST) grant by MSIP (Grant No. CAP-15-10-KRICT), and Korea University Future Research Grant. This work was also supported with supercomputing resources, including technical support (KSC-2016-C2-0021), by the National Institute of Supercomputing and Network/Korea Institute of Science and Technology Information. The synchrotron X-ray scattering measurements at the 4C SAXS II beamline of the Pohang Accelerator Laboratory were supported by the Ministry of Education and Science Technology. We acknowledge Korea Basic Science Institute (KBSI) for TEM measurements, and Agilent Technologies Inc. for support with the 6560 LC-IMS QTOFMS instrument and technical/scientific support. We also acknowledge Prof. Ho Hee Jang (Gachon University) for advices on performing cell viability assay and helpful discussion on the interpretation of the results.

    Publisher Copyright:
    © 2018 The Author(s).

    ASJC Scopus subject areas

    • General

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