Structural basis for leucine-rich nuclear export signal recognition by CRM1

CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 Å structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined α-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport. CRM1/snurportin-1 complex CRM1 is a nuclear transport receptor that mediates export of a large number of proteins out of the nucleus through recognition of leucine-rich nuclear export signals (LR-NES). In this study, Chook and colleagues present the crystal structure of CRM1 in complex with a substrate called snurportin1. Snurportin1 binds CRM1 in a bipartite manner through an N-terminal LR-NES and its nucleotide-binding domain. Further analysis reveals a second NES epitope in the nucleotide-binding domain of snurportin1. The authors propose that multipartite recognition of individually weak NES epitopes may be a common feature of CRM1 binding. The crystal structure of CRM1 in complex with a substrate called snurportin 1 is presented. Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal leucine-rich nuclear export signal (LR-NES) and its nucleotide-binding domain. Further analysis reveals a second NES epitope in the nucleotide-binding domain of snurportin 1, and multipartite recognition of individually weak NES epitopes may be a common feature of CRM1 binding.