Coil-to-Helix Transition at the Nup358-BicD2 Interface Activates BicD2 for Dynein Recruitment

Nup358, a nuclear pore protein, facilitates a nuclear positioning pathway that is essential for many biological processes, including neuromuscular and brain development. Nup358 binds and activates the auto-inhibited dynein adaptor Bicaudal D2 (BicD2), which in turn recruits and activates the dynein machinery to position the nucleus. However, the molecular details of the Nup358/BicD2 interaction remain poorly understood. Here, we show that a minimal Nup358 domain activates dynein/dynactin/BicD2 for processive motility on microtubules. Using nuclear magnetic resonance (NMR) titration and chemical exchange saturation transfer (CEST), a Nup358 helix encompassing residues 2162-2184 was identified, which transitioned from random coil to an -helix upon BicD2-binding and formed the core of the Nup358-BicD2 interface. Mutations in this region of Nup358 decreased the Nup358/BicD2 interaction, resulting in decreased dynein recruitment and impaired motility. BicD2 thus recognizes the cargo adaptor Nup358 though a "cargo recognition -helix", a structural feature that may stabilize BicD2 in its activated state and promote processive dynein motility.