Summary
Polonio et al. resolved the atomic structure of human RIPK1 amyloid fibrils using cryoprobe-detected solid-state NMR and cryo-EM. The fibrils adopt an N-shaped β-sheet fold stabilized by hydrogen bonding and hydrophobic packing. This architecture enables RIPK1 to nucleate RIPK3 fibrillization and MLKL oligomerization during necroptosis. The study shows that RIPK1 amyloids are functional scaffolds that regulate cell signaling, distinguishing them from pathological aggregates found in neurodegeneration. This structural state allows RIPK1 to act as a signaling switch between survival, apoptosis, and necroptosis depending on the cellular redox and caspase context.
Context
The concept of functional amyloid predates this paper, with early examples in bacterial curli fibers, Pmel17 melanin scaffolds, and prion-like CPEB in long-term memory. RIPK1 and RIPK3 were also known to form amyloid-like RHIM fibrils that transmit necroptotic signals. However, prior studies only showed morphology and dye binding without atomic detail. Polonio et al. (2025) present the first high-resolution structure of human RIPK1 amyloids, revealing the N-shaped β-sheet topology that explains how these fibrils assemble and disassemble in a regulated manner. This defines a new level of precision for how human stress-signaling kinases employ reversible amyloid architecture to control cell fate.
Mechanistic Link
In the stress–glutamate–ROS framework, RIPK1 represents the structural endpoint of excitotoxic stress. Cortisol-driven glutamatergic overactivation increases calcium influx, leading to mitochondrial ROS accumulation. When mitochondrial recovery fails, ROS and ATP depletion trigger RIPK1 activation through its kinase and RHIM domains. These domains assemble into amyloid fibrils that seed RIPK3 and initiate MLKL-mediated membrane rupture. The RHIM fibril acts as a physical scaffold translating biochemical overload into structural execution of necroptosis. This unites bioelectric hyperactivation, oxidative stress, and inflammatory cell death as sequential stages of the same energetic collapse.
Integration
Functional amyloids such as those formed by RIPK1 bridge stress signaling and degenerative pathology. Under transient conditions these fibrils are reversible and regulatory, but chronic oxidative stress converts them into persistent aggregates. This links excitotoxicity to neurodegeneration, where sustained glutamate signaling and cortisol exposure push signaling amyloids beyond recovery. The same mechanism likely contributes to the glial inflammatory amplification seen in ALS, Alzheimer, and other neurodegenerative conditions. RIPK1 amyloid formation therefore provides the structural proof of a shared stress-to-degeneration continuum across bioelectric, metabolic, and inflammatory systems.
β-Prone Segment Vulnerability
The β-sheet segments that form the RHIM fibril core are chemically sensitive to oxidation. Reactive oxygen species such as hydrogen peroxide and hydroxyl radicals attack side chains including methionine, cysteine, tyrosine, and tryptophan. When these residues are oxidized, their polarity and volume shift, breaking the hydrophobic packing that stabilizes the β-sheets. This causes local distortions and strand misalignment, fragmenting the fibril into smaller, unstable β-sheet pieces. Each fragment retains exposed hydrogen-bond edges that can seed new aggregates, turning a controlled scaffold into a self-propagating pathology. This process mirrors the oxidative fragmentation of tau filaments in Alzheimer disease. Both begin as reversible structural regulators and become irreversible debris under persistent oxidative pressure.
Material Basis
RIPK1 amyloids and tau filaments share the same molecular architecture of stacked β-strands forming cross-β hydrogen-bond networks. The difference lies in function and reversibility. RIPK1 amyloids form temporarily to mediate signaling and are normally dismantled by proteostasis systems. Tau filaments emerge when oxidation and phosphorylation prevent reversal, locking β-prone regions into permanent aggregates. Both structures represent the thermodynamic endpoint of peptide folding under stress. Excess ROS thus converts adaptive protein architecture into inert crystalline waste, bridging signaling failure and structural degeneration.
| Title | Authors | Year |
|---|---|---|
| Structural basis for amyloid fibril assembly by the master cell-signaling regulator receptor-interacting protein kinase 1 | Polonio et al. | 2025 |