Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals
Abstract
Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations. Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.
- Authors:
-
[1];
[1]
- Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Pharmacology
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Biological and Environmental Research (BER); Cancer Prevention Research Institute of Texas (CPRIT); Welch Foundation; Leukemia and Lymphoma Society Scholar Award; University of Texas Southwestern Endowed Scholars Program; Croucher Foundation Scholarship
- OSTI Identifier:
- 1510248
- Grant/Contract Number:
- AC02-06CH11357; RP120352; RP150053; R01 GM069909; I-1532
- Resource Type:
- Accepted Manuscript
- Journal Name:
- eLife
- Additional Journal Information:
- Journal Volume: 6; Journal Issue: 03, 2017; Journal ID: ISSN 2050-084X
- Publisher:
- eLife Sciences Publications, Ltd.
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Fung, Ho Yee Joyce, Fu, Szu-Chin, and Chook, Yuh Min. Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals. United States: N. p., 2017.
Web. doi:10.7554/eLife.23961.
Fung, Ho Yee Joyce, Fu, Szu-Chin, & Chook, Yuh Min. Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals. United States. https://doi.org/10.7554/eLife.23961
Fung, Ho Yee Joyce, Fu, Szu-Chin, and Chook, Yuh Min. Fri .
"Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals". United States. https://doi.org/10.7554/eLife.23961. https://www.osti.gov/servlets/purl/1510248.
@article{osti_1510248,
title = {Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals},
author = {Fung, Ho Yee Joyce and Fu, Szu-Chin and Chook, Yuh Min},
abstractNote = {Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations. Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.},
doi = {10.7554/eLife.23961},
journal = {eLife},
number = 03, 2017,
volume = 6,
place = {United States},
year = {Fri Mar 10 00:00:00 EST 2017},
month = {Fri Mar 10 00:00:00 EST 2017}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 49 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Identification of a signal for rapid export of proteins from the nucleus
journal, August 1995
- Wen, Wei; Meinkotht, Judy L.; Tsien, Roger Y.
- Cell, Vol. 82, Issue 3
Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia
journal, December 2016
- Alexander, Thomas B.; Lacayo, Norman J.; Choi, John K.
- Journal of Clinical Oncology, Vol. 34, Issue 34
Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies
journal, May 2016
- Hing, Z. A.; Fung, H. Y. J.; Ranganathan, P.
- Leukemia, Vol. 30, Issue 12
Evidence for a Role of CRM1 in Signal-Mediated Nuclear Protein Export
journal, October 1997
- Ossareh-Nazari, Batool; Bachelerie, Françoise; Dargemont, Catherine
- Science, Vol. 278, Issue 5335
Protein sequence requirements for function of the human T-cell leukemia virus type 1 Rex nuclear export signal delineated by a novel in vivo randomization-selection assay.
journal, August 1996
- Bogerd, H. P.; Fridell, R. A.; Benson, R. E.
- Molecular and Cellular Biology, Vol. 16, Issue 8
Fully Blind Peptide-Protein Docking with pepATTRACT
journal, August 2015
- Schindler, Christina E. M.; de Vries, Sjoerd J.; Zacharias, Martin
- Structure, Vol. 23, Issue 8
Prediction of leucine-rich nuclear export signal containing proteins with NESsential
journal, June 2011
- Fu, Szu-Chin; Imai, Kenichiro; Horton, Paul
- Nucleic Acids Research, Vol. 39, Issue 16
CRM1 is responsible for intracellular transport mediated by the nuclear export signal
journal, November 1997
- Fukuda, Makoto; Asano, Shiro; Nakamura, Takahiro
- Nature, Vol. 390, Issue 6657
CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications
journal, April 2013
- Tai, Y-T; Landesman, Y.; Acharya, C.
- Leukemia, Vol. 28, Issue 1
Identification of CRM1-dependent Nuclear Export Cargos Using Quantitative Mass Spectrometry
journal, December 2012
- Thakar, Ketan; Karaca, Samir; Port, Sarah A.
- Molecular & Cellular Proteomics, Vol. 12, Issue 3
CRM1 Blockade by Selective Inhibitors of Nuclear Export Attenuates Kidney Cancer Growth
journal, June 2013
- Inoue, Hiromi; Kauffman, Michael; Shacham, Sharon
- Journal of Urology, Vol. 189, Issue 6
Structural basis for leucine-rich nuclear export signal recognition by CRM1
journal, April 2009
- Dong, Xiuhua; Biswas, Anindita; Süel, Katherine E.
- Nature, Vol. 458, Issue 7242
Selective inhibitors of nuclear export (SINE)– a novel class of anti-cancer agents
journal, October 2014
- Parikh, Kaushal; Cang, Shundong; Sekhri, Arunabh
- Journal of Hematology & Oncology, Vol. 7, Issue 1
A Unified Conformational Selection and Induced Fit Approach to Protein-Peptide Docking
journal, March 2013
- Trellet, Mikael; Melquiond, Adrien S. J.; Bonvin, Alexandre M. J. J.
- PLoS ONE, Vol. 8, Issue 3
Structural diversity of calmodulin binding to its target sites
journal, May 2013
- Tidow, Henning; Nissen, Poul
- FEBS Journal, Vol. 280, Issue 21
A Novel Main Chain Motif in Proteins Bridged by Cationic Groups: The Niche
journal, January 2009
- Torrance, Gilleain M.; Leader, David P.; Gilbert, David R.
- Journal of Molecular Biology, Vol. 385, Issue 4
On the acquisition and analysis of microscale thermophoresis data
journal, March 2016
- Scheuermann, Thomas H.; Padrick, Shae B.; Gardner, Kevin H.
- Analytical Biochemistry, Vol. 496
LocNES: a computational tool for locating classical NESs in CRM1 cargo proteins
journal, December 2014
- Xu, Darui; Marquis, Kara; Pei, Jimin
- Bioinformatics, Vol. 31, Issue 9
Crystal Structure of the Nuclear Export Receptor CRM1 in Complex with Snurportin1 and RanGTP
journal, April 2009
- Monecke, T.; Guttler, T.; Neumann, P.
- Science, Vol. 324, Issue 5930
A nuclear export signal is essential for the cytosolic localization of the Ran binding protein, RanBP1
journal, September 1996
- Richards, S. A.
- The Journal of Cell Biology, Vol. 134, Issue 5
Detection and prognostic value of recurrent exportin 1 mutations in tumor and cell-free circulating DNA of patients with classical Hodgkin lymphoma
journal, June 2016
- Camus, V.; Stamatoullas, A.; Mareschal, S.
- Haematologica, Vol. 101, Issue 9
Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia
journal, November 2012
- Lapalombella, Rosa; Sun, Qingxiang; Williams, Katie
- Blood, Vol. 120, Issue 23
Selective inhibitors of nuclear export (SINE) in hematological malignancies
journal, March 2015
- Das, Arundhati; Wei, Guoqing; Parikh, Kaushal
- Experimental Hematology & Oncology, Vol. 4, Issue 1
Analysis and prediction of leucine-rich nuclear export signals
journal, June 2004
- la Cour, Tanja; Kiemer, Lars; Mølgaard, Anne
- Protein Engineering, Design and Selection, Vol. 17, Issue 6
Selective inhibitors of nuclear export (SINE) as novel therapeutics for prostate cancer
journal, July 2014
- Mendonca, Janet; Sharma, Anup; Kim, Hae-Soo
- Oncotarget, Vol. 5, Issue 15
Rosetta FlexPepDock ab-initio: Simultaneous Folding, Docking and Refinement of Peptides onto Their Receptors
journal, April 2011
- Raveh, Barak; London, Nir; Zimmerman, Lior
- PLoS ONE, Vol. 6, Issue 4
KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia
journal, February 2013
- Etchin, Julia; Sanda, Takaomi; Mansour, Marc R.
- British Journal of Haematology, Vol. 161, Issue 1
NESmapper: Accurate Prediction of Leucine-Rich Nuclear Export Signals Using Activity-Based Profiles
journal, September 2014
- Kosugi, Shunichi; Yanagawa, Hiroshi; Terauchi, Ryohei
- PLoS Computational Biology, Vol. 10, Issue 9
XPO1-dependent nuclear export is a druggable vulnerability in KRAS-mutant lung cancer
journal, September 2016
- Kim, Jimi; McMillan, Elizabeth; Kim, Hyun Seok
- Nature, Vol. 538, Issue 7623
Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia
journal, June 2011
- Puente, Xose S.; Pinyol, Magda; Quesada, Víctor
- Nature, Vol. 475, Issue 7354
First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors
journal, December 2016
- Abdul Razak, Albiruni R.; Mau-Soerensen, Morten; Gabrail, Nashat Y.
- Journal of Clinical Oncology, Vol. 34, Issue 34
NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1
journal, October 2010
- Güttler, Thomas; Madl, Tobias; Neumann, Piotr
- Nature Structural & Molecular Biology, Vol. 17, Issue 11
Sequence and structural analyses of nuclear export signals in the NESdb database
journal, September 2012
- Xu, Darui; Farmer, Alicia; Collett, Garen
- Molecular Biology of the Cell, Vol. 23, Issue 18
Structural principles that govern the peptide-binding motifs of class I MHC molecules 1 1Edited by I. Wilson
journal, September 1998
- Zhang, Chao; Anderson, Abraham; DeLisi, Charles
- Journal of Molecular Biology, Vol. 281, Issue 5
The Three-Dimensional Structure of Peptide-MHC Complexes
journal, April 1995
- Madden, Dean R.
- Annual Review of Immunology, Vol. 13, Issue 1
Identification of Novel Nuclear Export and Nuclear Localization-related Signals in Human Heat Shock Cognate Protein 70
journal, December 2003
- Tsukahara, Fujiko; Maru, Yoshiro
- Journal of Biological Chemistry, Vol. 279, Issue 10
Nuclear Export Signal Consensus Sequences Defined Using a Localization-Based Yeast Selection System
journal, December 2008
- Kosugi, Shunichi; Hasebe, Masako; Tomita, Masaru
- Traffic, Vol. 9, Issue 12
Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma
journal, September 2016
- Gounder, Mrinal M.; Zer, Alona; Tap, William D.
- Journal of Clinical Oncology, Vol. 34, Issue 26
XPO1 (CRM1) Inhibition Represses STAT3 Activation to Drive a Survivin-Dependent Oncogenic Switch in Triple-Negative Breast Cancer
journal, January 2014
- Cheng, Y.; Holloway, M. P.; Nguyen, K.
- Molecular Cancer Therapeutics, Vol. 13, Issue 3
The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
journal, October 2016
- Vercruysse, Thomas; De Bie, Jolien; Neggers, Jasper E.
- Clinical Cancer Research, Vol. 23, Issue 10
Calmodulin in Action
journal, March 2002
- Hoeflich, Klaus P.; Ikura, Mitsuhiko
- Cell, Vol. 108, Issue 6
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
- Jardin, Fabrice; Pujals, Anais; Pelletier, Laura
- American Journal of Hematology, Vol. 91, Issue 9
Fully Blind Docking at the Atomic Level for Protein-Peptide Complex Structure Prediction
journal, October 2016
- Yan, Chengfei; Xu, Xianjin; Zou, Xiaoqin
- Structure, Vol. 24, Issue 10
Nuclear transport of human immunodeficiency virus type 1, visna virus, and equine infectious anemia virus Rev proteins: identification of a family of transferable nuclear export signals.
journal, January 1996
- Meyer, B. E.; Meinkoth, J. L.; Malim, M. H.
- Journal of virology, Vol. 70, Issue 4
Works referencing / citing this record:
Engineering chromosome region maintenance 1 fragments that bind to nuclear export signals
journal, September 2019
- Lei, Yuqin; An, Qi; Zhang, Yuqing
- Protein Science, Vol. 29, Issue 6
Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization
journal, May 2018
- Pinarbasi, Emile S.; Cağatay, Tolga; Fung, Ho Yee Joyce
- Scientific Reports, Vol. 8, Issue 1
Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site
journal, April 2019
- Lee, Yoonji; Pei, Jimin; Baumhardt, Jordan M.
- Scientific Reports, Vol. 9, Issue 1
Nuclear export of ubiquitinated proteins via the UBIN-POST system
journal, April 2018
- Hirayama, Shoshiro; Sugihara, Munechika; Morito, Daisuke
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 18
Role of a versatile peptide motif in controlling Hox nuclear export and autophagy in the Drosophila fat body
posted_content, November 2019
- Duffraisse, Marilyne; Paul, Rachel; Hudry, Bruno
NoLogo: a new statistical model highlights the diversity and suggests new classes of Crm1-dependent nuclear export signals
journal, February 2018
- Liku, Muluye E.; Legere, Elizabeth-Ann; Moses, Alan M.
- BMC Bioinformatics, Vol. 19, Issue 1
Viral Appropriation: Laying Claim to Host Nuclear Transport Machinery
journal, June 2019
- Tessier, Tanner M.; Dodge, Mackenzie J.; Prusinkiewicz, Martin A.
- Cells, Vol. 8, Issue 6
Two Sides of the Coin: Ezrin/Radixin/Moesin and Merlin Control Membrane Structure and Contact Inhibition
journal, April 2019
- Michie, Katharine A.; Bermeister, Adam; Robertson, Neil O.
- International Journal of Molecular Sciences, Vol. 20, Issue 8
Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore
journal, May 2018
- Bao, Xun X.; Spanos, Christos; Kojidani, Tomoko
- eLife, Vol. 7
Exportin Crm1 is repurposed as a docking protein to generate microtubule organizing centers at the nuclear pore
posted_content, November 2017
- Bao, Xun X.; Spanos, Christos; Kojidani, Tomoko