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Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation

Journal Article · · Molecular Biology of the Cell
 [1];  [2];  [1];  [1];  [1];  [2];  [1];  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. The Ohio State Univ., Columbus, OH (United States)
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The E571K mutation of CRM1 is highly prevalent in some cancers, but its mechanism of tumorigenesis is unclear. Glu571 of CRM1 is located in its nuclear export signal (NES)-binding groove, suggesting that binding of select NESs may be altered. We generated HEK 293 cells with either monoallelic CRM1WT/E571K or biallelic CRM1E571K/E571K using CRISPR/Cas9. We also combined analysis of binding affinities and structures of 27 diverse NESs for wild-type and E571K CRM1 with structure-based bioinformatics. While most NESs bind the two CRM1 similarly, NESs from Mek1, eIF4E-transporter, and RPS2 showed >10-fold affinity differences. These NESs have multiple charged side chains binding close to CRM1 position 571, but this feature alone was not sufficient to predict different binding to CRM1(E571K). Consistent with eIF4E-transporter NES binding weaker to CRM1(E571K), eIF4E-transporter was mislocalized in tumor cells carrying CRM1(E571K). This serves as proof of concept that understanding how CRM1(E571K) affects NES binding provides a platform for identifying cargoes that are mislocalized in cancer upon CRM1 mutation. Finally, we showed that large affinity changes seen with some NES peptides (of Mek1 and RPS2) do not always translate to the full-length cargoes, suggesting limitations with current NES prediction methods. Therefore, comprehensive studies like ours are imperative to identify CRM1 cargoes with real pathogenic potential.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1659286
Alternate ID(s):
OSTI ID: 1810157
Journal Information:
Molecular Biology of the Cell, Journal Name: Molecular Biology of the Cell Journal Issue: 17 Vol. 31; ISSN 1059-1524
Publisher:
American Society for Cell BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (33)

Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma: XPO1 Mutations in Primary Mediastinal B-Cell Lymphoma journal July 2016
Regulating Access to the Genome journal February 2003
Karyopherins and nuclear import journal December 2001
On the acquisition and analysis of microscale thermophoresis data journal March 2016
Structural and Functional Characterization of CRM1-Nup214 Interactions Reveals Multiple FG-Binding Sites Involved in Nuclear Export journal October 2015
P-Body Purification Reveals the Condensation of Repressed mRNA Regulons journal October 2017
Structural basis for leucine-rich nuclear export signal recognition by CRM1 journal April 2009
Crm1 is a mitotic effector of Ran-GTP in somatic cells journal May 2005
Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site journal April 2019
Regulation of a nuclear export signal by an adjacent inhibitory sequence: The effector domain of the influenza virus NS1 protein journal April 1998
PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation journal July 2003
A role for the eIF4E-binding protein 4E-T in P-body formation and mRNA decay journal September 2005
Correlation of CRM1-NES affinity with nuclear export activity journal August 2018
NESdb: a database of NES-containing CRM1 cargoes journal September 2012
Sequence and structural analyses of nuclear export signals in the NESdb database journal September 2012
pCRM1exportome: database of predicted CRM1-dependent Nuclear Export Signal (NES) motifs in cancer-related genes journal August 2019
Leptomycin B-sensitive nuclear export of MAPKAP kinase 2is regulated by phosphorylation journal June 1998
A novel shuttling protein, 4E-T, mediates the nuclear import of the mRNA 5' cap-binding protein, eIF4E journal June 2000
4E-T-bound mRNAs are stored in a silenced and deadenylated form journal April 2020
HKL -3000: the integration of data reduction and structure solution – from diffraction images to an initial model in minutes journal July 2006
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Features and development of Coot journal March 2010
Nuclear Export Signal Consensus Sequences Defined Using a Localization-Based Yeast Selection System journal December 2008
Crystal Structure of the Nuclear Export Receptor CRM1 in Complex with Snurportin1 and RanGTP journal April 2009
The Structure of the Eukaryotic Ribosome at 3.0 A Resolution journal November 2011
Structural Biology of Nucleocytoplasmic Transport journal June 2007
Transport Between the Cell Nucleus and the Cytoplasm journal November 1999
Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis journal July 2019
Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines journal June 2008
Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia journal November 2012
Differential Regulation of Mitogen-Activated Protein/ERK Kinase (MEK)1 and MEK2 and Activation by a Ras-Independent Mechanism journal October 1997
Structural determinants of nuclear export signal orientation in binding to exportin CRM1 journal September 2015
Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals journal March 2017

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