Intrinsically disordered regions in the yeast transcriptional regulator Ixr1 support prion-like behavior

Ixr1 is a yeast transcriptional regulator previously identified as a player in the response to stress conditions, such as oxidative stress, hypoxia, iron limitation or DNA damage. Little is known about the structure of the Ixr1 protein apart from their HMG-boxes, which conform two well-known folded DNA binding domains. Intrinsically disordered regions (IDRs) are predicted in Ixr1 by algorithms and analytical methods. Ixr1 protein is non-globular and prone to aggregation, sustaining a concentration-dependent equilibrium between monomeric and dimeric forms. Treatment with 150 µM glutaraldehyde, to stabilize and fix weak protein-protein interactions, induces Ixr1 to form large oligomers. Indeed, Ixr1 forms amyloids as demonstrated both by in vitro and in vivo approaches. Chimeras constructed between Ixr1 and the C-terminal domain of Sup35, which provides the translation termination function to the yeast prion [PSI⁺], show that IDRs from Ixr1 substitute the N-terminal region of Sup35 that is responsible of its priogenic nature. Finally, Artificial Intelligence (AI) assisted modeling of Ixr1 with Ssn8 (Srb11), which was already identified as a protein interacting with Ixr1 and related to yeast stress response, reveals that their interaction might diminish the disordered/priogenic nature of Ixr1 and increase the Ixr1 folding in the heterodimer.