Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

The functional switch of glutamine/asparagine (Q/N)-rich prions and the neurotoxicity of polyQ-expanded proteins involve complex aggregation-prone structural transitions, commonly presumed to be forming β sheets. By analyzing sequences of interaction partners of these proteins, we discovered a recurrent presence of coiled-coil domains both in the partners and in segments that flank or overlap Q/N-rich and polyQ domains. Since coiled coils can mediate protein interactions and multimerization, we studied their possible involvement in Q/N-rich and polyQ aggregations. Using circular dichroism and chemical crosslinking, we found that Q/N-rich and polyQ peptides form α-helical coiled coils in vitro and assemble into multimers. Using structure-guided mutagenesis, we found that coiled-coil domains modulate in vivo properties of two Q/N-rich prions and polyQ-expanded huntingtin. Mutations that disrupt coiled coils impair aggregation and activity, whereas mutations that enhance coiled-coil propensity promote aggregation. These findings support a coiled-coil model for the functional switch of Q/N-rich prions and for the pathogenesis of polyQ-expansion diseases. [Display omitted] ► Many interactors of Q/N-rich prions and polyQ proteins contain coiled-coil domains ► Q/N-rich and polyQ domains have sequence features of α-helical coiled-coil structures ► α-Helical Q/N-rich and polyQ peptides form oligomers and multimers in vitro ► Q/N-rich and polyQ coiled-coils promote protein aggregation and activity in vivo