The Role of Variable Repetitive Protein Domainsin Azf1p Function and Prion Formation

Abstract

Prions are naturally occurring, self‐propagating isoforms of proteins that represent a heritable mechanism for tuning protein function. The yeast transcription factor Azf1p was recently demonstrated to form a prion, [AZF1+], that confers resistance to the drug radicicol but reduces Azf1p target gene expression. Using the Prion‐Like Amino Acid Composition tool, we identified regions of Azf1p that are predicted to contribute to prion formation. Two notable candidates are the polyglutamine (polyQ) and polyasparagine (polyN) domains. Through a bioinformatic analysis of the genomes of 93 lab and wild isolates of S. cerevisiae, we determined that these domains vary in repeat copy number across strains of yeast. The polyQ domain has two alleles, while the polyN domain has six alleles ranging from 17 to 25 N residues. In this work, we are investigating the extent to which the variable polyQ and polyN domains of Azf1p play a role in its transcription factor activity and contribute to [AZF1+] prion formation. This research determines the effects of repeat‐length variation on protein localization and stability, prion activity, and target gene expression.Support or Funding InformationThis work is supported by the Army Research Office (W911NF‐19‐1‐0299)