Membrane charge primes the necroptotic kinase RIPK3 for amyloid assembly
Abstract Receptor-interacting protein kinase 3 (RIPK3) drives necroptosis by assembling into functional amyloid fibrils. Here we show that lipids modulate RIPK3 amyloidogenesis by stabilizing an aggregation-prone intermediate. While electrostatic repulsion maintains RIPK3 in a soluble state, charge...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-025-01658-0 |
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| Summary: | Abstract Receptor-interacting protein kinase 3 (RIPK3) drives necroptosis by assembling into functional amyloid fibrils. Here we show that lipids modulate RIPK3 amyloidogenesis by stabilizing an aggregation-prone intermediate. While electrostatic repulsion maintains RIPK3 in a soluble state, charge compensation alone is not sufficient for fibril formation and hydrophobic contacts are required to initiate nucleation. Using solution-state NMR, fluorescence-based assays and polymer-encased lipid particles, we demonstrate that negatively charged membranes selectively recruit RIPK3 and restrict its conformational flexibility, accelerating aggregation. These findings reveal a membrane-guided mechanism for RIPK3 assembly and suggest that lipid surfaces, like those implicated in pathological amyloid formation, may modulate functional amyloidogenesis even in the absence of canonical necroptotic stimuli. |
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| ISSN: | 2399-3669 |