Untethering the Nuclear Envelope and Cytoskeleton: Biologically Distinct Dystonias Arising from a Common Cellular Dysfunction

Figure 3

Hypothesized model for torsinA, dystonin-a2, and their common associated partner, nesprin-3α. This schematic represents the associations between torsinA and dystonin-a2 with nesprin-3α , a type II TM protein in the ONM that contains a C-terminal KASH domain within the lumenal space of the NE. Nesprin-3α interacts with SUN proteins (green and gray), which span the INM of the NE, through its KASH domain (purple). TorsinA (red hexameric circles) associates with nesprin-3α and regulates its interaction with SUN proteins. The N-terminus of nesprin-3α binds to the plakin family member, plectin, which in turn links to IFs through its IF-binding domain (IFBD; blue). Dystonin-a2 has a TM domain (dark blue) at the N-terminus, which embeds in the ONM of the NE and associates with nesprin-3α. Like plectin, dystonin-a isoforms are members of the plakin protein family and are characterized by SR domains indicated by the “chain shape” (gray) and an ABD (pink) in the N-terminal region. The dystonin-a2 isoform also possesses a C-terminal MTBD through which it associates with microtubules. Collectively, these proteins function to bridge the NE and ER with the three major cytoskeleton networks present in eukaryotes.