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.
Escobedo-González et al. (Tue,) studied this question.