Fig. P1.

Proposed model for length discrimination by MDA5. MDA5 filaments switch continuously between assembly and disassembly phases in the presence of ATP. Because disassembly occurs primarily from the filament ends, filaments on short dsRNA undergo complete disassembly more frequently, requiring slow de novo nucleation for rebinding. In contrast, filaments on long dsRNA alternate between partial disassembly and fast elongation, consequently bypassing nucleation. Thus, slow nucleation kinetics amplifies the effect of length-dependent dissociation kinetics of MDA5 and prevents the accumulation of MDA5 on short dsRNAs and aberrant activation of antiviral signaling.