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Proc. Natl. Acad. Sci. USA, Feb 04 2025, 122 (5) | https://doi.org/10.1073/pnas.2408582122 Structural insights into the role of reduced cysteine residues in SOD1 amyloid filament formation

Yeongjin Baek^{1 †}, Hyunmin Kim ^{2 3 †}, Dukwon Lee ¹, Doyeon Kim ¹, Eunbyul Jo ¹, Soung-Hun Roh ^{2 *}, Nam-Chul Ha ^{1 4 *}

¹Department of Agricultural Biotechnology, and Research Institute of Agriculture and Life Sciences, CALS, Seoul National University, Seoul 08826, Republic of Korea.
²School of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Seoul 08826, Republic of Korea.
³Molecular Systems Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany.
⁴Center for Food and Bioconvergence, Seoul National University, Seoul 08826, Republic of Korea.

^†These authors contributed equally
^*Corresponding author: correspondence to Soung-Hun Roh or Nam-Chul Ha

Abstract

The formation of superoxide dismutase 1 (SOD1) filaments has been implicated in amyotrophic lateral sclerosis (ALS). Although the disulfide bond formed between Cys57 and Cys146 in the active state has been well studied, the role of the reduced cysteine residues, Cys6 and Cys111, in SOD1 filament formation remains unclear. In this study, we investigated the role of reduced cysteine residues by determining and comparing cryoelectron microscopy (cryo-EM) structures of wild-type (WT) and C6A/C111A SOD1 filaments under thiol-based reducing and metal-depriving conditions, starting with protein samples possessing enzymatic activity. The C6A/C111A mutant SOD1 formed filaments more rapidly than the WT protein. The mutant structure had a unique paired-protofilament arrangement, with a smaller filament core than that of the single-protofilament structure observed in WT SOD1. Although the single-protofilament form developed more slowly, cross-seeding experiments demonstrated the predominance of single-protofilament morphology over paired protofilaments, regardless of the presence of the Cys6 and Cys111 mutations. These findings highlight the importance of the number of amino acid residues within the filament core in determining the energy requirements for assembly. Our study provides insights into ALS pathogenesis by elucidating the initiation and propagation of filament formation, which potentially leads to deleterious amyloid filaments.

논문정보

형식Research article
게재일2025년 02월 (BRIC 등록일 2025-02-03)
연구진국내(교신)+국외 연구진
분야 생명과학 > 구조생물 및 생물물리학

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