Thus, the SUN proteins represent links in a molecular chain that connects elements of the cytoskeleton to components within the nucleus. that are either depleted of Sun1 by RNA interference or that overexpress dominant-negative Sun1 fragments exhibit clustering of NPCs. The implication is that Sun1 represents an important determinant of NPC distribution across the nuclear surface. Introduction The nuclear envelope (NE) is the selective barrier that defines the Piperidolate hydrochloride interface between the nucleus and the cytoplasm (Burke and Stewart, 2002; Gruenbaum et al., 2005). Because it mediates molecular trafficking between these two compartments, it plays an essential role in the maintenance of their biochemical identities. In addition to its transport function, the NE is also a key determinant of nuclear architecture, providing anchoring Piperidolate hydrochloride sites at the nuclear periphery for chromatin domains as well as for a variety of structural and regulatory molecules. A corresponding contribution to cytoplasmic structure has been described in which NE components may also influence cytoskeletal organization and mechanotransduction (Tzur et al., 2006; Worman and Gundersen, 2006). The NE is composed of several structural elements, the most prominent of which are the inner nuclear membranes (INMs) and outer nuclear membranes (ONMs). These are separated by the perinuclear space (PNS), a gap of 30C50 nm. Annular junctions between the INM and ONM create aqueous channels that traverse the NE and that are occupied by nuclear pore complexes (NPCs). It is the NPCs that endow the NE with its selective transport properties (Tran and Wente, 2006). The final major feature of the NE is the nuclear lamina, a thin (20C50 nm) Piperidolate hydrochloride protein layer that is associated with both the INM and chromatin. The lamina is composed primarily of A- and B-type lamins, which are members of the intermediate filament protein family (Gerace et al., 1978). The lamins interact with components of the INM and NPCs as well as with chromatin proteins and DNA (Zastrow et al., 2004). In this way, the lamina plays an important Piperidolate hydrochloride structural and organizational role at the nuclear periphery. Despite their continuities, the INM and ONM are biochemically distinct. The ONM features numerous junctions with the peripheral ER, to which it is functionally and compositionally similar. In contrast, the INM contains its own unique selection of integral proteins. Clearly, the INM, ONM, and ER represent discrete domains within a single continuous membrane system. Accordingly, the PNS is a perinuclear extension of the ER lumen. Localization of integral proteins to the INM involves a process of selective retention (Powell and Burke, 1990; Soullam and Worman, 1995; Ellenberg et al., 1997). Although proteins that are mobile within the ER and ONM may gain access to the INM via the continuities at each NPC, only proteins that interact with nuclear or other NE components are retained and concentrated. Recent studies suggest that additional mechanisms may overlie this basic scheme. Ohba et al. (2004) showed that movement of integral proteins through the NPC membrane domain is energy dependent. Other studies suggest a role for the nuclear transport receptor adaptor karyopherin/importin- in the transit of proteins to the INM (King et al., 2006; Saksena et al., 2006). Recognition of ONM-specific membrane proteins raises the question of what prevents these proteins from escaping to the peripheral ER. In ONM protein, (Welte et al., 1998; Mosley-Bishop et al., 1999), in that they contain an 50Camino acid C-terminal KASH (Klarsicht, Anc-1, Syne homology) domain consisting of a single transmembrane (TM) anchor and a short segment of 30C40 residues that resides within the PNS. A third ONM KASH domainCcontaining protein, nesprin 3, interacts with plectin, which is a large (466 kD) cytolinker (Wilhelmsen et al., 2005). KRT20 Unc-84 contains an 200Camino acidity C-terminal area that shares.