FC0011
Myosin VI  -  Actin filament

Biological function
Myosin VI is a molecular motor, which is widely expressed in different tissues and is also involved in endocytosis. It moves processively along actin and dimers take multiple steps on actin filaments.

Structural evidence
EM shows that the observed distance between the centers of the two heads of myosine VI construct is 27 ± 6 nm. This value is greater than expected if the two heads were held together at the C terminal end of the IQ/CaM domain, where the heads should span no more than ~18 nm. EM shows that the proximal tail alone does not act as a rigid extension of the lever arm. Instead, the proximal tail acts as a flexible linker connecting the heads.

Biochemical evidence
Insertion of GCN4 into the proximal tail domain yields steps that are both shorter and more regular in comparison to myosine VI construct, highlighting the key role of the proximal tail in the diffusive search.

Structure/Mechanism
The step size is larger than anticipated, ~36 nm, which is enabled by the ’proximal tail’. This tail is not a rigid lever arm, it has unusual flexibility. The elastic properties of the proximal tail can be described by a Worm Chain-like (WML) model, even though the tail has some α-helical propensity. This enables a diffusive search along actin facilitated by electrostatic interactions between the highly tail and the filament. As described by a simple mechanical model, the proximal tail extends from 24 nm to reach the 36 nm step-size. The α-helical propensity of the proximal tail can increase the persistence length and lower the stiffness. This would in turn lower the energetic barrier and facilitate the diffusive search. In addition, the proximal tail is highly charged (pI 10.2, net charge of +5), which may function as a means of electrostatic steering of an unbound head and might even provide binding of the flexible linker to the actin filament in the poststroke state.

Mechanism category
tethering

Significance
Fuzzy segments enable the step-size mechanism to find new electrostatic interactions. The flexible coupling is necessary for the load-induced switching from motor activity to an anchor. Another possibility is that this motor is designed to straddle neighboring actin filaments in its role in the inner ear or in endocytosis, and therefore needs unusual flexibility.