Crystal Structure of the Nuclear Export Receptor CRM1 in Complex with Snurportin1 and RanGTP

Nuclear Import/Export Receptor Nuclear transport receptors constantly shuttle cargo between the nucleus and the cytoplasm through nuclear pore complexes. In the nucleus, RanGTP promotes the dissociation of cargo from importins, which import cargo into the nucleus (where RanGTP is guanosine 5′ triphosphate–bound Ran). Conversely, nuclear RanGTP promotes cargo-binding to exportins, which export cargo from the nucleus. Cargo is released from exportins in the cytoplasm upon hydrolysis of RanGTP. Cytoplasmically assembled RNA splicing components enter the nucleus together with an import adapter snurportin 1 (SPN1), but how then does the import adapter release its cargo and exit the nucleus to collect further cargo? The nuclear exportin CRM1 exports a broad range of substrates—including SPN1, ribosomes, and many regulatory proteins. Monecke et al. (p. 1087) describe the crystal structure of CRM1 bound to SPN1 and RanGTP. The structure shows that SPN1 cannot simultaneously bind its import cargo and the exportin CRM1, ensuring that only cargo-free SPN1 is returned to the cytoplasm. There are no direct contacts between Ran and SPN1 in the ternary complex, suggesting that RanGTP promotes cargo-binding through long-range conformational changes in CRM1. The structure of an exportin complex shows how nuclear transport complexes differentially recognize cargo. CRM1 mediates nuclear export of numerous unrelated cargoes, which may carry a short leucine-rich nuclear export signal or export signatures that include folded domains. How CRM1 recognizes such a variety of cargoes has been unknown up to this point. Here we present the crystal structure of the SPN1⋅CRM1⋅RanGTP export complex at 2.5 angstrom resolution (where SPN1 is snurportin1 and RanGTP is guanosine 5′ triphosphate–bound Ran). SPN1 is a nuclear import adapter for cytoplasmically assembled, m3G-capped spliceosomal U snRNPs (small nuclear ribonucleoproteins). The structure shows how CRM1 can specifically return the cargo-free form of SPN1 to the cytoplasm. The extensive contact area includes five hydrophobic residues at the SPN1 amino terminus that dock into a hydrophobic cleft of CRM1, as well as numerous hydrophilic contacts of CRM1 to m3G cap-binding domain and carboxyl-terminal residues of SPN1. The structure suggests that RanGTP promotes cargo-binding to CRM1 solely through long-range conformational changes in the exportin.