LINC complexes, as well as their subunit Nesprin-1/2 are essential for brain development. Nesprin-1 is a paralog of Nesprin-2, with some unique and some shared functions. To position the nucleus during brain development for neuronal migration, Nesprin-2 interacts with the microtubules motors dynein and kinesin-1 that are recruited via bicaudal D2 (BicD2), but the structural details of these interactions are elusive. Here, the structural model of a minimal Nesprin-2/BicD2 complex was obtained from AlphaFold and experimentally validated by biophysical studies, mutagenesis of the contact residues and binding assays. Two spectrin repeats of Nesprin-2 form an alpha-helical bundle with BicD2 that is structurally distinct from other BicD2/cargo complexes. Such structural differences could modulate motility of the associated motors dynein and kinesin-1 for these transport pathways. Notably, the Nesprin-2 fragment activates dynein/dynactin/BicD2 complexes that contain full-length BicD2 for processive motility, suggesting that no additional components are required to reconstitute this transport pathway. The kinesin-1 binding site is spatially close but does not overlap with the dynein/BicD2 recruitment site, therefore dynein and kinesin-1 may bind to Nesprin-2 simultaneously. Emery-Dreifuss muscular dystrophy is caused by several mutations of Nesprin-1 and Nesprin-2 that are found in the motor-recruiting domain and may possibly alter interactions with the motors and BicD2. Nuclear positioning by this pathway is required for normal muscle development, as abnormally clustered nuclei have been found in patients with Emery-Dreifuss muscular dystrophy. Furthermore, several human BicD2 disease mutations that cause spinal muscular atrophy alter its affinity toward Nesprin-2 and modulate this transport pathway that is essential for brain development. A preprint reporting these results is available on BioRxiv at the following link: https://doi.org/10.1101/2025.05.18.654709.
Putta et al. (Sun,) studied this question.
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