Abstract
Proteins bearing a leucine-rich nuclear export signal (NES) are exported from the nucleus by the transport factor CRM1, which forms a cooperative ternary complex with the NES-bearing cargo and with the small GTPase Ran. CRM1-mediated export is regulated by RanBP3, a Ran-interacting nuclear protein. Unlike the related proteins RanBP1 and RanBP2, which promote disassembly of the export complex in the cytosol, RanBP3 acts as a CRM1 cofactor, enhancing NES export by stabilizing the export complex in the nucleus. RanBP3 also alters the cargo selectivity of CRM1, promoting recognition of the NES of HIV-1 Rev and of other cargos while deterring recognition of the import adaptor protein Snurportin1. Here we report the crystal structure of the Ran-binding domain (RBD) from RanBP3 and compare it to RBD structures from RanBP1 and RanBP2 in complex with Ran and CRM1. Differences among these structures suggest why RanBP3 binds Ran with unusually low affinity, how RanBP3 modulates the cargo selectivity of CRM1, and why RanBP3 promotes assembly rather than disassembly of the export complex. The comparison of RBD structures thus provides an insight into the functional diversity of Ran-binding proteins.
Highlights
CRM1/Exportin1, a member of the importin-b/karyopherin-b family of nuclear transport factors, is responsible for exporting many proteins and ribonucleoproteins from the nucleus to the cytosol [1,2,3,4]
Macromolecular cargos exported by CRM1 are characterized by a leucine-rich nuclear export signal (NES), a short, loosely conserved motif first discovered in HIV-1 Rev and protein kinase A inhibitor (PKI) and subsequently identified in over 75 cellular and viral proteins [5,6,7]
CRM1-mediated export is dependent on the small GTPase Ran, whose nucleotide-bound state is regulated by the Ran GTPase-activating protein (RanGAP) and by the guanine nucleotide exchange factor RCC1 [8,9]
Summary
CRM1/Exportin, a member of the importin-b/karyopherin-b family of nuclear transport factors, is responsible for exporting many proteins and ribonucleoproteins from the nucleus to the cytosol [1,2,3,4]. CRM1 associates in a cooperative manner with RanGTP and with the NES-bearing cargo to form a ternary CRM1/Ran/cargo complex that translocates through the nuclear pore complex (NPC) and subsequently dissociates in the cytosol. The crystal structures of human CRM1 in binary complex with Spn and in ternary complex with Ran and Spn revealed that CRM1 consists of 20 tandem HEAT repeats [14,15]. These approximately 50-residue motifs comprise two anti-parallel helices (designated A and B) that pack against each other and against neighbouring repeats to form an elongated solenoid [16]. Details of cargo recognition have been further elucidated by structures of CRM1 bound to PKI- and Rev-type NESs [17]
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