Research

We have discovered a disordered protein sequence in Ty1 that is similar to sequences implicated in transmissible and neurodegenerative mammalian diseases (e.g., Alzheimer's, Parkinson's, Huntington's, Creutzfeld-Jakob disease). This prion-like domain is required for Ty1 to build virus-like particles (VLPs) (Beckwith et al, 2023, PNAS). Our work suggests a mechanism for nucleating VLP assembly that may be widespread across transposons and viruses and establishes an in vivo platform to study disordered protein sequences involved in neurodegeneration and other diseases using the extensive genetic toolkit developed for Ty1 in yeast.

Uncontrolled replication of Ty1 retrotransposons can be deleterious to the host and is restricted by a self-encoded protein called p22. To prevent excessive Ty1 replication and genomic damage, p22 disrupts virus-like particle (VLP) function by interaction with the Ty1 Gag protein. Disrupting VLP assembly prevents reverse transcription and retrotransposition. We uncovered the molecular basis of p22 restriction by solving the crystal structure of a minimal fragment of p22. Our data suggest how p22 can function in restriction through a blocking-of-assembly mechanism to inhibit VLP assembly by creating dead-end intermediates in the assembly pathway (Cottee & Beckwith et al, 2021, Nature Communications). We then elucidated the molecular determinants of restriction specificity in two closely related Ty1 subfamily transposons (Beckwith & Cottee et al, 2025, PLOS Genetics), which may inform the rational design of blocking-of-assembly inhibitors for disease-relevant retrotransposons, retroviruses, and domesticated capsid genes in mammalian genomes.