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<p>Amyloid assembly is governed by a balance between intrinsic sequence determinants and environmental cues that modulate nucleation. The RIP homotypic interaction motif (RHIM) of receptor-interacting protein kinase 3 (RIPK3) provides a tractable model to dissect these principles. In solution, amyloid formation strictly requires the conserved VQVG RHIM core tetrad; a deliberately core-disrupted variant (VQVG→AAAA) fails to assemble under aggregation permissive conditions. Here, we use Thioflavin-T fluorescence assays and NMR spectroscopy to show that negatively charged lipidic interfaces unlock a latent amyloidogenic potential in this mutant. These results delineate two separable dimensions of amyloidogenesis, namely a sequence-encoded propensity and an environmental component that can catalyze nucleation by templating molecular proximity and orientation.</p>

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Charged membrane interfaces reshape the nucleation landscape of RIPK3 amyloid variants

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月10日

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  • Fátima C. Escobedo-González,
  • Andrea Gelardo,
  • Gustavo A. Titaux-Delgado,
  • Miguel Mompeán

摘要

Amyloid assembly is governed by a balance between intrinsic sequence determinants and environmental cues that modulate nucleation. The RIP homotypic interaction motif (RHIM) of receptor-interacting protein kinase 3 (RIPK3) provides a tractable model to dissect these principles. In solution, amyloid formation strictly requires the conserved VQVG RHIM core tetrad; a deliberately core-disrupted variant (VQVG→AAAA) fails to assemble under aggregation permissive conditions. Here, we use Thioflavin-T fluorescence assays and NMR spectroscopy to show that negatively charged lipidic interfaces unlock a latent amyloidogenic potential in this mutant. These results delineate two separable dimensions of amyloidogenesis, namely a sequence-encoded propensity and an environmental component that can catalyze nucleation by templating molecular proximity and orientation.