NESdb: a database of NES-containing CRM1 cargoes

Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390.
Molecular biology of the cell (Impact Factor: 5.98). 07/2012; 23(18):3673-6. DOI: 10.1091/mbc.E12-01-0045
Source: PubMed

ABSTRACT The leucine-rich nuclear export signal (NES) is the only known class of targeting signal that directs macromolecules out of the cell nucleus. NESs are short stretches of 8-15 amino acids with regularly spaced hydrophobic residues that bind the export karyopherin CRM1. NES-containing proteins are involved in numerous cellular and disease processes. We compiled a database named NESdb that contains 221 NES-containing CRM1 cargoes that were manually curated from the published literature. Each NESdb entry is annotated with information about sequence and structure of both the NES and the cargo protein, as well as information about experimental evidence of NES-mapping and CRM1-mediated nuclear export. NESdb will be updated regularly and will serve as an important resource for nuclear export signals. NESdb is freely available to nonprofit organizations at

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Available from: Yuh Min Chook, Dec 21, 2014
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    • "CRM1 is among seven exportins, and the only one that mediates the transport of over 230 proteins including tumor suppressors (e.g., p53, p73, and FOXO1), growth regulator/pro-inflammatory (e.g., IkB, Rb, p21, p27, BRCA1, and APC), and anti-apoptotic proteins (e.g., NPM and AP-1) (Table 1, the aforementioned proteins are part of a comprehensive list appearing on the web page: Academics/IndexFiles/names.php) (Kau et al., 2004; Turner et al., 2012; Xu et al., 2012). CRM1 is also required for the transport of several mRNAs, proteins, and rRNAs that are essential for ribosomal biogenesis (Thomas & Kutay, 2003; Golomb et al., 2012; Bai et al., 2013; Tabe et al., 2013). "
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    ABSTRACT: Nucleocytoplasmic trafficking of proteins/RNAs is essential to normal cellular function. Indeed, accumulating evidence suggests that cancer cells escape anti-neoplastic mechanisms and benefit from pro-survival signals via the dysregulation of this system. The nuclear exporter chromosome region maintenance 1 (CRM1) protein is the only protein in the karyopherin-β protein family that contributes to the trafficking of numerous proteins and RNAs from the nucleus. It is considered to be an oncogenic, anti-apoptotic protein in transformed cells, since it reportedly functions as a gatekeeper for cell survival, including affecting p53 function, and ribosomal biogenesis. Furthermore, abnormally high expression of CRM1 is correlated with poor patient prognosis in various malignancies. Therapeutic targeting of CRM1 has emerged as a novel cancer treatment strategy, starting with a clinical trial with leptomycin B, the original specific inhibitor of CRM1, followed by development of several next-generation small molecules. KPT-330, a novel member of the CRM1-selective inhibitors of nuclear export (SINE) class of compounds, is currently undergoing clinical evaluation for the therapy of various malignancies. Results from these trials suggest that SINE compounds may be particularly useful against hematological malignancies, which often become refractory to standard chemotherapeutic agents. Copyright © 2015. Published by Elsevier Inc.
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    • "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, I␬B␣ and Survivin [37] [38] [39] [40] [41]. "
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    ABSTRACT: CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers and quite a few of its cargos are misregulated in the diseases and hence mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes the structure-function studies that explain CRM1-cargo recognition, release and inhibition.
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    ABSTRACT: We compiled >200 nuclear export signal (NES)-containing CRM1 cargoes in a database named NESdb. We analyzed the sequences and three-dimensional structures of natural, experimentally identified NESs and of false-positive NESs that were generated from the database in order to identify properties that might distinguish the two groups of sequences. Analyses of amino acid frequencies, sequence logos, and agreement with existing NES consensus sequences revealed strong preferences for the Φ1-X(3)-Φ2-X(2)-Φ3-X-Φ4 pattern and for negatively charged amino acids in the nonhydrophobic positions of experimentally identified NESs but not of false positives. Strong preferences against certain hydrophobic amino acids in the hydrophobic positions were also revealed. These findings led to a new and more precise NES consensus. More important, three-dimensional structures are now available for 68 NESs within 56 different cargo proteins. Analyses of these structures showed that experimentally identified NESs are more likely than the false positives to adopt α-helical conformations that transition to loops at their C-termini and more likely to be surface accessible within their protein domains or be present in disordered or unobserved parts of the structures. Such distinguishing features for real NESs might be useful in future NES prediction efforts. Finally, we also tested CRM1-binding of 40 NESs that were found in the 56 structures. We found that 16 of the NES peptides did not bind CRM1, hence illustrating how NESs are easily misidentified.
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