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  • We thank Dr Hongqiang Qin at Dalian Institute of

    2021-06-10

    We thank Dr. Hongqiang Qin at Dalian Institute of Chemical Physics, Chinese Academy of Sciences for technical assistance in mass-spectrometric analysis. We thank Prof. Quentin Liu at Dalian Medical University and Prof. Qiang Shen at M.D. Anderson Cancer Center for helpful discussion and comments. Dr. Y. Yang's laboratory was supported by the Fundamental Research Funds for the Central Universities (grant: DUT15QY43) and Dr. Cladribine australia C. Li laboratory was supported by grants from Peking-Tsinghua Center for Life Sciences.
    Introduction Nucleocytoplasmic transport is an essential process that governs the localization of numerous proteins and RNAs in eukaryotic cells. While small molecules can diffuse passively across through the nuclear pore complex (NPC), the majority of macromolecular transport across the nuclear envelope is mediated by nuclear transport receptors of the Karyopherin β (Kap) family. There are 19 known Kaps in human Cladribine australia and they include import receptors called Importins, export receptors called Exportins and bidirectional Kaps that have both Importin and Exportin functions [1], [2], [3], [4], [5], [6], [7], [8], [9]. Kap proteins share low sequence identities (10–20%) but have similar physical properties such as molecular weights (90–150kDa) and isoelectric points (pI=4.0–5.0) [10]. Nuclear transport is achieved through interactions of cargos with Kap proteins, which in turn interact with nucleoporins that make up the NPC. Kap-cargo interactions are controlled by the GTPase Ran. There are seven known Exportins in human cells. Of these, CRM1 (Chromosome region maintenance 1, also known as Exportin-1 or XPO1) is the most general and prevalently used export receptor. Other Exportins such as Cas, Exportin-t and Exportin-5 seem to be more specialized as they primarily export the import adaptor Importin-α, tRNAs and pre-miRNAs, respectively [11], [12], [13]. CRM1 was first identified through a mutation in its gene, which caused distortion in chromosome structure in Schizosaccharomyces pombe and was thus named Chromosomal Region Maintenance 1 [14]. CRM1 was later found to be an essential nuclear export receptor [15], [16], [17], [18], [19], [20], [21]. The discovery of CRM1's nuclear export function was also accompanied by the finding that the natural product inhibitor Leptomycin B (LMB) is a very potent and specific inhibitor of CRM1 [17], [22], [23]. LMB facilitated the identification of numerous CRM1 cargos [24]. Like other Kaps, CRM1 also uses the Ran GTPase to load and unload cargos [25]. CRM1 binds cooperatively with cargos and RanGTP to form export complexes in the nucleus, which then translocate through the NPC via CRM1-nucleoporin interactions [21], [26], [27], [28], [29], [30]. CRM1 recognizes its export cargos through nuclear export signals or NESs in their polypeptide chains known as classical- or leucine-rich-NESs. These export signals are stretches of 8–15 amino acids, which contain patterns of hydrophobic residues [31], [32], [33], [34], [35]. Approximately 300 functionally diverse CRM1 cargos have been reported in the literature and information about these NES-containing proteins are archived in databases such as NESdb and ValidNESs [24], [36]. CRM1 cargos include many tumor suppressors and cell growth regulators such as p53, BRCA1/2, FOXO3, IκBα and Survivin [37], [38], [39], [40], [41]. Many of these cargo proteins are misregulated and then mislocalized to the cytoplasm in cancer cells [42]. CRM1 itself is also overexpressed in several malignancies and high levels of CRM1 protein is associated with lower survival rates in the patients [43], [44], [45], [46], [47], [48]. CRM1 has recently been shown to be an effective drug target for various cancers as CRM1 inhibition restores nuclear localization and nuclear functions of tumor suppressors, leading to apoptosis of the cancer cells [43], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63]. Atomic level understanding of CRM1 function obtained from numerous structural studies was critical in the drug discovery endeavor to target this essential cellular process.