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  • BET bromodomain inhibitor sale Common to all models for nucl

    2019-10-31

    Common to all models for nuclear transport is the binding of importins/exportins to FG repeats found in about a third of the ∼30 nucleoporins, the so-called FG-Nups (Iovine et al., 1995, Rexach and Blobel, 1995); for review, see Grossman et al. (2012), Stewart (2007), and Terry and Wente (2009). FG-Nups in general are important for NPC function (Strawn et al., 2004), and FG-Nups that delineate the transport channel play important roles in the formation of the permeability barrier of the NPC (Hülsmann et al., 2012). FG-Nups located at the cytoplasmic filaments of the NPC were suggested as initial or terminal BET bromodomain inhibitor sale for transport complexes (Kehlenbach et al., 1999, Yokoyama et al., 1995). The best-characterized transport receptor with respect to FG-Nup binding is importin β (Chi et al., 1997, Kose et al., 1997, Kutay et al., 1997). Crystal structures of an importin β fragment with FG peptides revealed a hydrophobic interaction of the peptides with the outer surface of the N-terminal region of importin β (Bayliss et al., 2000, Bayliss et al., 2002, Liu and Stewart, 2005). BET bromodomain inhibitor sale A second nucleoporin-binding site was identified in the C-terminal half of importin β. Molecular dynamics simulations suggested that many more nucleoporin interaction sites are present in importin β (Isgro and Schulten, 2005) and probably in other transport receptors as well. Crystal structures of transport receptors showing multiple interactions with nucleoporins, however, are not available so far. FG-rich regions of nucleoporins are usually not resolved in crystal structures, most likely because they tend to be natively unfolded (Denning et al., 2003) and may only adopt a defined structure upon interaction with a binding partner. CRM1 is the most-prominent nuclear export receptor (Fornerod et al., 1997a, Fukuda et al., 1997, Kehlenbach et al., 1998, Ossareh-Nazari et al., 1997). It transports hundreds of different proteins harboring nuclear export signals (NESs) out of the nucleus and is also a major factor in RNA export (Hutten and Kehlenbach, 2007). CRM1 consists of an array of 21 HEAT repeats and adopts an overall pitched and superhelical conformation in its free form (Monecke et al., 2013). Cargo and/or RanGTP-bound CRM1 changes its conformation toward a closed ring-like or toroidal shape, where the N- and C-terminal arches interact (Dong et al., 2009a, Dong et al., 2009b, Güttler et al., 2010, Monecke et al., 2009). CRM1 binds RanGTP on the interior with major contributions of N-terminal HEAT repeats 1–6 (H1–6) in addition to residues of the acidic loop, a long β-hairpin in H9 (Monecke et al., 2009). In contrast, the cargo SPN1 is bound on the outer surface and interacts with CRM1 via the N-terminal NES, the central cap-binding domain, and the C-terminal 12 residues (Dong et al., 2009b, Monecke et al., 2009). Formation of the export complex in the nucleus is a rate-limiting step in nuclear export (Kehlenbach et al., 2001), and several factors have been identified that promote the formation of CRM1-containing complexes. The best-characterized factor is the Ran-binding protein RanBP3 (Yrb2p in yeast), which binds directly to CRM1 and enhances its affinity for RanGTP and for NES cargoes (Englmeier et al., 2001, Lindsay et al., 2001). Similar effects have been suggested for the nucleoporins Nup98 (Oka et al., 2010) and NLP1/hCG1 (Waldmann et al., 2012). The nucleoporin with the highest affinity for CRM1 is Nup214 (von Lindern et al., 1990), which localizes to the cytoplasmic side of the NPC (Panté et al., 1994). An FG repeat region within the C terminus of Nup214 is required for its interaction with CRM1 (Fornerod et al., 1996, Fornerod et al., 1997b), and several FG motifs contribute to efficient binding (Roloff et al., 2013). CRM1 binding to Nup214 is promoted by RanGTP (Kehlenbach et al., 1999), suggesting that the nucleoporin is involved in a late step of nuclear export. Depletion of Nup214 resulted in inhibition of nuclear export of some, but not all, CRM1-dependent cargoes (Bernad et al., 2006, Hutten and Kehlenbach, 2006). Nup214 stabilizes the interaction between the export receptor, RanGTP, and the transport cargo (Hutten and Kehlenbach, 2006), although the significance of synaptic vesicles effect of a cytoplasmic nucleoporin remains unclear.