Emerging role of NOMO and ER mechanobiology. (A) Overview of key cellular mechanotransduction and force-bearing elements, including focal adhesions, the plasma membrane, cytoskeleton, nuclear envelope, and nuclear interior, along with the emerging role of the ER. (B) Schematic structure of the ER protein NOMO in its compact form, in which the Ig-like domains Ig1 and Ig10-Ig11 interact via salt bridges, and in the extended form when the salt bridges are disrupted (top). Numbers indicate the position of the Ig-like domains. The bottom panel shows different putative forms in which NOMO could be organized within the ER, including those with intramolecular salt bridges (left) and intermolecular salt bridges (center and right). Note that NOMO is predicted to form dimers, independent of the salt bridges, but for simplicity, only monomers are shown here for most configurations. (C) Phenotypes associated with NOMO depletion or when disrupting the interface required to form Ig1-Ig10/11 interactions. These include voids in the ER network (red arrows), increased mobility of NOMO within the ER, and muscle defects.