Cascarina Sean M, Paul Kacy R, Ross Eric D
a Department of Biochemistry and Molecular Biology , Colorado State University , Fort Collins , CO , USA.
Prion. 2017 Sep 3;11(5):323-331. doi: 10.1080/19336896.2017.1356560.
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.
在理解有利于酵母中朊病毒形成的蛋白质特征方面取得的重大进展，推动了有效的酵母朊病毒预测算法的开发。在此，我们讨论一项近期研究，在该研究中我们系统地探究了酵母朊病毒预测算法PAPA在设计突变以调节人类朊病毒样蛋白hnRNPA2B1的聚集活性方面的效用。hnRNPA2B1中的突变会导致人类多系统蛋白病，并在体外加速该蛋白的聚集。此外，突变型hnRNPA2B1在果蝇中表达时会形成细胞质内含物，并且突变的朊病毒样结构域可以替代酵母朊病毒结构域的一部分来支持酵母中的朊病毒活性。PAPA在预测PrLD突变对酵母中朊病毒活性和体外聚集倾向的影响方面相当成功。此外，当在果蝇中表达时，PAPA成功预测了hnRNPA2B1蛋白PrLD中大多数（但不是全部）突变的影响。这些结果表明，PAPA在预测突变对内在聚集倾向的影响方面相当有效，但细胞内因素可以在体内影响聚集和朊病毒样活性。对这些细胞内因素的更全面理解可能会为下一代朊病毒预测算法提供信息。
