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Title: Correlation of CRM1-NES affinity with nuclear export activity

Journal Article · · Molecular Biology of the Cell
 [1];  [1];  [1];  [1];  [1]
  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
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CRM1 (Exportin1/XPO1) exports hundreds of broadly functioning protein cargoes out of the cell nucleus by binding to their classical nuclear export signals (NESs). The 8- to 15-amino-acid-long NESs contain four to five hydrophobic residues and are highly diverse in both sequence and CRM1-bound structure. Here we examine the relationship between nuclear export activities of 24 different NES peptides in cells and their CRM1-NES affinities. We found that binding affinity and nuclear export activity are linearly correlated for NESs with dissociation constants (Kds) between tens of nanomolar to tens of micromolar. NESs with Kds outside this range have significantly reduced nuclear export activities. These include two unusually tight-binding peptides, one from the nonstructural protein 2 of murine minute virus (MVM NS2) and the other a mutant of the protein kinase A inhibitor (PKI) NES. The crystal structure of CRM1-bound MVM NS2NES suggests that extraordinarily tight CRM1 binding arises from intramolecular contacts within the NES that likely stabilizes the CRM1-bound conformation in free peptides. This mechanistic understanding led to the design of two novel peptide inhibitors that bind CRM1 with picomolar affinity.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE; Cancer Prevention Research Institute of Texas; National Institutes of Health (NIH); Welch Foundation
Grant/Contract Number:
RP150053; RP170170; RP180410; R01 GM069909; I-1532
OSTI ID:
1570748
Journal Information:
Molecular Biology of the Cell, Vol. 29, Issue 17; ISSN 1059-1524
Publisher:
American Society for Cell BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 23 works
Citation information provided by
Web of Science

References (26)

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Design of Peptide Inhibitors for the Importin α/β Nuclear Import Pathway by Activity-Based Profiling journal September 2008
Evidence for a Role of CRM1 in Signal-Mediated Nuclear Protein Export journal October 1997
Structure of importin-α bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein journal October 2015
NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1 journal October 2010
CRM1 is responsible for intracellular transport mediated by the nuclear export signal journal November 1997
CRM1 Is an Export Receptor for Leucine-Rich Nuclear Export Signals journal September 1997
Identification of CRM1-dependent Nuclear Export Cargos Using Quantitative Mass Spectrometry journal December 2012
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On the acquisition and analysis of microscale thermophoresis data journal March 2016
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Structural basis for assembly and disassembly of the CRM1 nuclear export complex journal April 2009
LocNES: a computational tool for locating classical NESs in CRM1 cargo proteins journal December 2014
A Supraphysiological Nuclear Export Signal Is Required for Parvovirus Nuclear Export journal June 2008
Molecular basis for specificity of nuclear import and prediction of nuclear localization journal September 2011
Structure-based design of a pathway-specific nuclear import inhibitor journal April 2007
Synergy of two low-affinity NLSs determines the high avidity of influenza A virus nucleoprotein NP for human importin α isoforms journal September 2017
Exportin 1 (Crm1p) Is an Essential Nuclear Export Factor journal September 1997
Crystallographic Analysis of the Recognition of a Nuclear Localization Signal by the Nuclear Import Factor Karyopherin α journal July 1998
A Minimal Nuclear Localization Signal (NLS) in Human Phospholipid Scramblase 4 That Binds Only the Minor NLS-binding Site of Importin α1 journal June 2011
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ValidNESs: a database of validated leucine-rich nuclear export signals journal October 2012
Structural determinants of nuclear export signal orientation in binding to exportin CRM1 journal September 2015
A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning journal December 2015
Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals journal March 2017

Cited By (3)

Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site journal April 2019
Ciliary proteins Fap43 and Fap44 interact with each other and are essential for proper cilia and flagella beating journal April 2018
Diverse opportunities for immunologists journal February 1997

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