Disassembly of MDA5 filament is both ATP and RNA length-dependent. (A) Time-dependent EMSA monitoring of MDA5∶RNA complex dissociation. The reaction was initiated by adding a mixture of 2 mM ATP (or ADPCP or no ligand) and 200 μg/mL heparin to MDA5 (1.35 μM) in complex with 512 bp dsRNA (1.2 μg/mL, 0.32 μM MDA5 binding site), quenched on ice at indicated time points and analyzed on native gel. (B) Single-round ATP hydrolysis kinetics (mean ± SD, n = 3) of WT MDA5 (0.1 μM) with and without K335A or D443A (0.1 μM) bound to 512 bp dsRNA (1.2 μg/mL) with and without heparin (hep, 200 μg/mL). (C) Time evolution of the ATP hydrolysis rate derived from the single-round kinetics (Fig. S5F) of WT MDA5 (0.2 μM) bound to 512, 1,012, and 2,012 bp dsRNAs (1.2 μg/mL) using the finite difference method. The rates were normalized against the initial rate during the first 15 s. (D) Single-round ATP hydrolysis rate of WT MDA5 (0.1 μM) with K335A or D443A (0.1 μM) bound to 512, 1,012, and 2,012 bp dsRNAs (1.2 μg/mL) in the presence of heparin (200 μg/mL) during 4–10 min. No ATP hydrolysis was observed without the mutants during this time period.