(A) Speculative model for how a high-affinity NES cargo could become docked at the cytoplasmic face of the nuclear pore complex (NPC). In diagrams, only the FG-repeat region of Nup146 is shown; by analogy to Sc Nup159, Nup146 is assumed to be anchored at the cytoplasmic face of the NPC by interaction of its C-terminal domain with partners Nup82 and Nsp1. Binding of Crm1 to cargo, RanGTP and Nup146 FG repeats all contribute cooperatively to Crm1 compact conformation. Therefore, 1) if cargo has only low affinity for Crm1, then after partial release of Nup146 FG repeats from Crm1, the trimeric export complex (Crm1, cargo and RanGTP) can disassemble, releasing cargo into the cytoplasm. However, 2) if cargo has a high affinity for Crm1, then stabilization of the Crm1 compact conformation by cargo binding allows partially released FG repeats to rebind to Crm1. Increased stability of interaction between trimeric complex and Nup146 FG repeats leads to increased residence time at the cytoplasmic face of the NPC. See main text for further details. (B) ‘Cargo-handover’ as a potential mechanism for incorporating high-affinity NES cargos from the cytoplasm into export-like complexes at the cytoplasmic face of NPCs. First, a conventional nuclear export complex with a low-affinity NES cargo transiently interacts with Nup146 FG repeats during passage through the NPC. Recent integrated structural analysis in budding yeast suggests that FG repeats of Sc Nup159 may be directly adjacent to the symmetric FG-Nups at the centre of the NPC (Fernandez-Martinez et al., 2016); therefore, even though Nup146 FG repeats are not required for export, some proportion of export complexes could be expected to interact with Nup146 during passage through the NPC. Second, low-affinity cargo dissociates from Crm1, while Crm1 remains bound to Nup146 and to RanGTP. Dissociation of low-affinity cargo could be either spontaneous or aided by RanBP1; in both cases, this could occur without dissociation or hydrolysis of RanGTP (Koyama and Matsuura, 2010). In absence of cargo, compact Crm1 conformation (and RanGTP binding) may be partially stabilized by interaction with Nup146 FG repeats, as has been shown for FG repeats of Hs Nup214 (Hutten and Kehlenbach, 2006). Finally, during a ‘window of opportunity’ before dissociation of Crm1 from Nup146, a high-affinity NES cargo such as the Mto1 NES-M can bind to Crm1 to generate the export-like complex.