MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation

A disordered to beta -sheet transition was thought to drive the functional switch of Q/N-rich prions, similar to pathogenic amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) regions within yeast prion domains in amyloid formation. We show that many human prion-like domains (PrLDs) contain CC regions that overlap with polyQ tracts. Most of the proteins bearing these domains are transcriptional coactivators, including the Mediator complex subunit 15 (MED15) involved in bridging enhancers and promoters. We demonstrate that the human MED15-PrLD forms homodimers in solution sustained by CC interactions and that it is this CC fold that mediates the transition towards a beta -sheet amyloid state, its chemical or genetic disruption abolishing aggregation. As in functional yeast prions, a GFP globular domain adjacent to MED15-PrLD retains its structural integrity in the amyloid state. Expression of MED15-PrLD in human cells promotes the formation of cytoplasmic and perinuclear inclusions, kidnapping endogenous full-length MED15 to these aggregates in a prion-like manner. The prion-like properties of MED15 are conserved, suggesting novel mechanisms for the function and malfunction of this transcription coactivator. Batlle et al. identify the presence of coiled-coil (CC) domains that overlap with polyQ tracts in human proteins containing prion-like domains (PrLDs). They demonstrate that human MED15 Mediator complex subunit forms homodimers in solution mediated by coiled-coil interactions and that MED15CC aggregates into amyloid fibrils.

Automated summary

Recent evidence suggests that coiled-coil (CC) regions overlapping with polyQ tracts play a critical role in amyloid formation and functional switch in human proteins. The human MED15 Mediator complex subunit forms homodimers in solution mediated by CC interactions, with MED15CC aggregating into amyloid fibrils.