SUN domain-containing protein 2 (SUN2) is a nuclear inner membrane protein and a component of the linker of the nucleoskeleton and cytoskeleton (LINC) complex, which plays critical roles in nuclear positioning, cell polarisation and cellular stiffness []. SUN2 contains a conserved Sad1p/UNC-84 (SUN)-domain at its C terminus that can associate with Klarsicht/ANC-1/Syne homology (KASH)-domain proteins []. The structure of the LINC complex has been solved []. In mammals, SUN2 is widely expressed and can bind to all four Nesprins (KASH-domain containing proteins) [].
LINC complexes are formed by coupling of KASH (Klarsicht, ANC-1, and Syne/Nesprin Homology) and SUN (Sad1 and UNC-84) proteins from the inner and outer nuclear membranes (INM and ONM, respectively). The formation of LINC complexes by KASH and SUN proteins at the nuclear envelope (NE) establishes the physical linkage between the cytoskeleton and nuclear lamina, which is instrumental for the mechanical force transmission from the cytoplasm to the nuclear interior, and is essential for cellular processes such as nuclear positioning and migration, centrosome-nucleus anchorage, and chromosome dynamics. SUN2 possesses two coiled-coil domains (CC1 and CC2). These coiled-coil domains are also believed to act as rigid spacers to delineate the distance between the ONM and INM of the NE. Furthermore, the two coiled-coil domains of SUN2 have been indicated to be able to directly modulate SUN domain activity and regulate the subsequent interactions between the SUN and KASH domains. CC2 forms a three-helix bundle to lock the SUN domain in an inactive conformation acting as an inhibitory component. Structure-based sequence analysis demonstrated that several Gly residues are located in the flexible linker regions between the three helices which would ideally provide the breaks/turns in CC2 for three-helix bundle formation. The last helix alpha3 of CC2 (that is immediately connected to the SUN domain) has been shown to be an essential segment for promoting SUN domain trimerization in the SUN-KASH complex structure [, ].
