Correlation of CRM1-NES affinity with nuclear export activity

Szu Chin Fu, Ho Yee Joyce Fung, Tolga Caǧatay, Jordan Baumhardt, Yuh Min Chook

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 (K d s) between tens of nanomolar to tens of micromolar. NESs with K d s 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 NS2 NES 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.

Original languageEnglish (US)
Pages (from-to)2037-2044
Number of pages8
JournalMolecular biology of the cell
Issue number17
StatePublished - Aug 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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