Scholarlink

<p>Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial Amyotrophic Lateral Sclerosis (ALS), promoting disease progression through metal depletion, aggregation, and abnormal protein interactions. Among proteins interacting with pathological SOD1 aggregates, 14-3-3 proteins are involved in key cellular pathways often disrupted in ALS, such as cell survival, axonal growth, and DNA repair. Their sequestration by mutant SOD1 may impair their neuroprotective functions, exacerbating disease pathology. Despite this, 14-3-3 proteins remain understudied in ALS research, presenting an opportunity for novel insights. This study employs molecular dynamics simulations to investigate structural changes in two ALS-linked SOD1 mutations, A4V and L144F, compared to wild-type SOD1. A4V is associated with a severe disease form, while L144F leads to a slower progression, allowing an analysis of different ALS severities. Using Zernike polynomials and hydropathy assessments, we identified key structural alterations that promote aggregation and aberrant interactions. Large-scale docking simulations further suggest a stable complex between mutant SOD1 and 14-3-3 proteins, confirmed through molecular dynamics analyses. By elucidating structural features driving SOD1 aggregation and pathological interactions, our findings support targeting protein-protein interactions as a potential therapeutic strategy in ALS, offering an alternative to direct aggregate inhibition.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Uncovering the molecular details of the 14-3-3 recruitment by mutant Sod1 species

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月20日

查看全文
  • Lorenzo Di Rienzo,
  • Ilaria Genovese,
  • Gaia Galluzzi,
  • Giancarlo Ruocco,
  • Ersilia Fornetti

摘要

Mutations in superoxide dismutase 1 (SOD1) are a major cause of familial Amyotrophic Lateral Sclerosis (ALS), promoting disease progression through metal depletion, aggregation, and abnormal protein interactions. Among proteins interacting with pathological SOD1 aggregates, 14-3-3 proteins are involved in key cellular pathways often disrupted in ALS, such as cell survival, axonal growth, and DNA repair. Their sequestration by mutant SOD1 may impair their neuroprotective functions, exacerbating disease pathology. Despite this, 14-3-3 proteins remain understudied in ALS research, presenting an opportunity for novel insights. This study employs molecular dynamics simulations to investigate structural changes in two ALS-linked SOD1 mutations, A4V and L144F, compared to wild-type SOD1. A4V is associated with a severe disease form, while L144F leads to a slower progression, allowing an analysis of different ALS severities. Using Zernike polynomials and hydropathy assessments, we identified key structural alterations that promote aggregation and aberrant interactions. Large-scale docking simulations further suggest a stable complex between mutant SOD1 and 14-3-3 proteins, confirmed through molecular dynamics analyses. By elucidating structural features driving SOD1 aggregation and pathological interactions, our findings support targeting protein-protein interactions as a potential therapeutic strategy in ALS, offering an alternative to direct aggregate inhibition.