Effects of Mutations on the Aggregation Propensity of the Human Prion-Like Protein hnRNPA2B1

ABSTRACT

Hundreds of human proteins contain prion-like domains, which are a subset of low-complexity domains with high amino acid compositional similarity to yeast prion domains. A recently characterized mutation in the prion-like domain of the human heterogeneous nuclear ribonucleoprotein hnRNPA2B1 increases the aggregation propensity of the protein and causes multisystem proteinopathy. The mutant protein forms cytoplasmic inclusions when expressed in Drosophila, the mutation accelerates aggregation in vitro, and the mutant prion-like domain can substitute for a portion of a yeast prion domain in supporting prion activity. To examine the relationship between amino acid sequence and aggregation propensity, we made a diverse set of point mutations in the hnRNPA2B1 prion-like domain. We found that the effects on prion formation in Saccharomyces cerevisiae and aggregation in vitro could be predicted entirely based on amino acid composition. However, composition was an imperfect predictor of inclusion formation in Drosophila; while most mutations showed similar behaviors in yeast, in vitro, and in Drosophila, a few showed anomalous behavior. Collectively, these results demonstrate the significant progress that has been made in predicting the effects of mutations on intrinsic aggregation propensity while also highlighting the challenges of predicting the effects of mutations in more complex organisms.

KEYWORDS:

• aggregation
• low-complexity domain
• prion-like
• prions

This article is referred to by:

Manipulating the aggregation activity of human prion-like proteins

ACKNOWLEDGMENTS

This work was supported by grants from the National Science Foundation (MCB-1517231) and National Institutes of Health (GM105991) to E.D.R. and NIH grant R35NS097974 to J.P.T. The microscopes used for the yeast work and electron microscopy are supported by the Microscope Imaging Network core infrastructure grant from Colorado State University.

We thank Kim Vanderpool for assistance with electron microscopy.