Fig. 6: Importance of a folded monomer for regulation.

a When auto-inhibited, Myo6 can diffuse across actin-rich regions and interacts weakly with F-actin. These weak actin interactions (~7 µM apparent affinity, estimated in Supplementary Fig. 4E) result in facilitated diffusion and in increasing the Myo6 concentration in actin-rich regions of the cell. Once recruited by a partner, Myo6 is activated and starts performing its cellular function. b Scheme representing possible activation mechanisms for Myo6. Myo6 domains are color-coded: Myo6 MD (gray), Ins2/CaM (purple), IQ/CaM (red/pink), 3HB in blue, SAH (green), DT (orange), CBD (brown), and the partner binding sites (garnet). The binding site (WWY) for Dab2 and TOM1 is blocked, preventing recruitment of Myo6 without a prior unfolding signal prior to unblock their binding. GIPC1 can bind the accessible RRL motif resulting in Myo6 recruitment and opening. Other signals can act as unfolding factors such as Ca²⁺, which can allow TOM1 to bind to Myo6. Such an activation cascade was previously proposed³⁶. Once unfolded, Myo6 potentially acts as a monomer, as previously proposed³⁵ upon TOM1 binding; or it can dimerize²⁹ through proximal dimerization, as demonstrated in this study with GIPC1 binding; or it dimerizes through distal dimerization upon Dab2 binding¹³, which may lead to proximal dimerization.