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

2009; Nature Portfolio; Volume: 458; Issue: 7242 Linguagem: Inglês

10.1038/nature07975

1476-4687

Xiuhua Dong, Anindita Biswas, Katherine E. Süel, Laurie K. Jackson, Rita Martinez, Hongmei Gu, Yuh Min Chook,

DNA Repair Mechanisms

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 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.