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Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion

Author

Listed:
  • Li-Qiang Wang

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

  • Yeyang Ma

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Han-Ye Yuan

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

  • Kun Zhao

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Mu-Ya Zhang

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

  • Qiang Wang

    (Huazhong Agricultural University)

  • Xi Huang

    (Jinan University (Shenzhen People’s Hospital))

  • Wen-Chang Xu

    (Wuhan University)

  • Bin Dai

    (Shanghai Jiao Tong University)

  • Jie Chen

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

  • Dan Li

    (Shanghai Jiao Tong University
    Shanghai Jiao Tong University)

  • Delin Zhang

    (Huazhong Agricultural University)

  • Zhengzhi Wang

    (Wuhan University)

  • Liangyu Zou

    (Jinan University (Shenzhen People’s Hospital))

  • Ping Yin

    (Huazhong Agricultural University)

  • Cong Liu

    (Chinese Academy of Sciences)

  • Yi Liang

    (Wuhan University
    Wuhan University Shenzhen Research Institute)

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. Misfolded Cu, Zn-superoxide dismutase (SOD1) has been linked to both familial and sporadic ALS. SOD1 fibrils formed in vitro share toxic properties with ALS inclusions. Here we produced cytotoxic amyloid fibrils from full-length apo human SOD1 under reducing conditions and determined the atomic structure using cryo-EM. The SOD1 fibril consists of a single protofilament with a left-handed helix. The fibril core exhibits a serpentine fold comprising N-terminal segment (residues 3–55) and C-terminal segment (residues 86–153) with an intrinsic disordered segment. The two segments are zipped up by three salt bridge pairs. By comparison with the structure of apo SOD1 dimer, we propose that eight β-strands (to form a β-barrel) and one α-helix in the subunit of apo SOD1 convert into thirteen β-strands stabilized by five hydrophobic cavities in the SOD1 fibril. Our data provide insights into how SOD1 converts between structurally and functionally distinct states.

Suggested Citation

  • Li-Qiang Wang & Yeyang Ma & Han-Ye Yuan & Kun Zhao & Mu-Ya Zhang & Qiang Wang & Xi Huang & Wen-Chang Xu & Bin Dai & Jie Chen & Dan Li & Delin Zhang & Zhengzhi Wang & Liangyu Zou & Ping Yin & Cong Liu , 2022. "Cryo-EM structure of an amyloid fibril formed by full-length human SOD1 reveals its conformational conversion," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31240-4
    DOI: 10.1038/s41467-022-31240-4
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    References listed on IDEAS

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    1. Lynn Radamaker & Julian Baur & Stefanie Huhn & Christian Haupt & Ute Hegenbart & Stefan Schönland & Akanksha Bansal & Matthias Schmidt & Marcus Fändrich, 2021. "Cryo-EM reveals structural breaks in a patient-derived amyloid fibril from systemic AL amyloidosis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
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