It Takes KASH to Hitch to the SUN

Observations stretching back more than two decades have suggested that nuclei and nuclear components are mechanically coupled to the cytoskeleton. In multicellular organisms, this mechanical coupling may extend beyond the plasma membrane to the extracellular matrix and adjacent cells. More recently, studies on a variety of human diseases associated with defects in nuclear envelope (NE) proteins have revealed that, not only can the cytoskeleton affect nuclear organization, but changes in nuclear architecture may have a reciprocal affect on cytoskeletal function (Burke and Roux, 2009). In this issue, Sosa et al. (2012) provide an atomic resolution description of key interactions at the NE that link nuclear and cytoplasmic components. The most prominent features of the NE are inner and outer nuclear membranes (INM and ONM) separated by a gap, or perinuclear space (PNS), of about 40–50 nm. The two membranes are spanned by nuclear pore complexes at annular junctions. The ONM also displays connections to the endoplasmic reticulum (ER). In this way, the ER, ONM, and INM represent separate domains within a single continuous membrane system, with the PNS forming an extension of the ER lumen. Whereas the INM contains a unique array of membrane proteins, the composition of the ONM closely resembles that of the ER. Nevertheless, the ONM is enriched in several integral membrane proteins that function as adapters for a variety of cytoskeletal components, including motor proteins. In vertebrate cells, these ONM proteins are represented, in part, by members of the Nesprin or Syne family. The common feature of all known ONM-specific proteins, including Nesprins, is a C-terminal KASH (Klarsicht, Anc1, Syne homology) domain of 50–60 amino acid residues (Burke and Roux, 2009). The KASH domain consists of a single-membrane spanning helix followed by a sequence of about 30 residues that extends into the PNS. Localization of KASH domain proteins to the ONM is dependent upon interaction with integral proteins of the INM that belong to the SUN (Sad1p, Unc84) domain family. In mammalian cells, there are two widely expressed SUN domain proteins, Sun1 and Sun2. The SUN domain itself is a highly conserved 200 amino acid C-terminal sequence that resides within the PNS at the end of a helical ‘‘stalk’’ and can interact directly with KASH domains of ONM proteins. In this way, proteins such as Sun1 and Sun2 function as transluminal tethers for Nesprin proteins in the ONM. The nucleoplasmic domains of SUN proteins are associated with a variety of nuclear components, including the nuclear lamina, an important structural feature of the NE that is closely associated with both the INM and underlying