# Cargo Recognition of Nesprin‑2 by the Dynein Adapter Bicaudal D2 for a Nuclear Positioning Pathway That Is Important for Brain Development

## TL;DR

This study reveals how Nesprin-2 interacts with BicD2 to position the nucleus during brain development, using structural models and experiments.

## Contribution

The paper provides structural insights into the Nesprin-2/BicD2 interaction and its role in nuclear positioning during brain development.

## Key findings

- Nesprin-2 binds to BicD2 via spectrin repeats, forming an α-helical bundle distinct from other BicD2 complexes.
- Nesprin-2 activates dynein/dynactin/BicD2 complexes for processive motility without additional components.
- Mutations in Nesprin-1 and 2 linked to muscular dystrophy may disrupt interactions with kinesin-1 and BicD2/dynein.

## Abstract

Nesprin-2 and its paralog Nesprin-1 are subunits of LINC
complexes
that are essential for brain development. To position the nucleus
for neuronal migration, Nesprin-2 interacts with the motors kinesin-1
and dynein, which are recruited by the adapter Bicaudal D2 (BicD2),
but the molecular details of these interactions are elusive. Here,
structural models of minimal Nesprin-2/BicD2 complexes with 1:2 and
2:2 stoichiometry were predicted using AlphaFold and experimentally
validated by mutagenesis, binding assays, and single-molecule biophysical
studies. The core of the binding site is formed by spectrin repeats
of Nesprin-2, which form an α-helical bundle with BicD2 that
is structurally distinct from the Rab6/BicD2 and Nup358/BicD2 complexes.
Such structural differences could fine-tune the motility of associated
dynein and kinesin-1 motors for these transport pathways. Furthermore,
the Nesprin-2 fragment interacts with full-length BicD2 and activates
dynein/dynactin/BicD2 complexes for processive motility, suggesting
that no additional components are required to reconstitute this transport
pathway. Interestingly, either one or two Nesprin-2 molecules can
bind to a BicD2 dimer and activate BicD2/dynein/dynactin complexes
for processive motion, resulting in similar speed and run lengths.
The BicD2/dynein binding site is spatially close but does not overlap
with the kinesin-1 recruitment site, thus both motors may interact
with Nesprin-2 simultaneously. Several mutations of Nesprin-1 and
2 that cause Emery–Dreifuss muscular dystrophy are found in
the motor-recruiting domain and may alter interactions with kinesin-1
and BicD2/dynein, consistent with the abnormally positioned nuclei
found in patients with this disease.