Manipulating the aggregation activity of human prion-like proteins

Abstract

Considerable advances in understanding the protein features favoring prion formation in yeast have facilitated the development of effective yeast prion prediction algorithms. Here we discuss a recent study in which we systematically explored the utility of the yeast prion prediction algorithm PAPA for designing mutations to modulate the aggregation activity of the human prion-like protein hnRNPA2B1. Mutations in hnRNPA2B1 cause multisystem proteinopathy in humans, and accelerate aggregation of the protein in vitro. Additionally, mutant hnRNPA2B1 forms cytoplasmic inclusions when expressed in Drosophila, and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity in yeast. PAPA was quite successful at predicting the effects of PrLD mutations on prion activity in yeast and on in vitro aggregation propensity. Additionally, PAPA successfully predicted the effects of most, but not all, mutations in the PrLD of the hnRNPA2B1 protein when expressed in Drosophila. These results suggest that PAPA is quite effective at predicting the effects of mutations on intrinsic aggregation propensity, but that intracellular factors can influence aggregation and prion-like activity in vivo. A more complete understanding of these intracellular factors may inform the next generation of prion prediction algorithms.

Keywords: amyloid; prion; prion-like domains; protein aggregation; yeast.

FIGURE 1.

Intracellular processes commonly affecting PrLD aggregation. Mutations, changes in protein concentration, or post-translational modifications in PrLDs can affect protein aggregation by altering intrinsic aggregation propensity (1); liquid-liquid phase separation/stress granule dynamics (2); conversion of granules to a pathological state (3); organism-, tissue-, or compartment-specific intermolecular interactions (4); proteasome-mediated degradation (5); or nucleocytoplasmic transport (6).