Structural basis for leucine-rich nuclear export signal recognition by CRM1

Nature. 2009 Apr 30;458(7242):1136-41. doi: 10.1038/nature07975. Epub 2009 Apr 1.

Abstract

CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 A structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus
  • Crystallography, X-Ray
  • Epitopes
  • Fatty Acids, Unsaturated / pharmacology
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Karyopherins / chemistry*
  • Karyopherins / metabolism*
  • Leucine / metabolism*
  • Models, Molecular
  • Nuclear Export Signals / physiology*
  • Protein Binding / drug effects
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Structure-Activity Relationship
  • Substrate Specificity
  • snRNP Core Proteins / chemistry
  • snRNP Core Proteins / metabolism

Substances

  • Epitopes
  • Fatty Acids, Unsaturated
  • Karyopherins
  • Nuclear Export Signals
  • Receptors, Cytoplasmic and Nuclear
  • exportin 1 protein
  • snRNP Core Proteins
  • Leucine
  • leptomycin B

Associated data

  • PDB/3GB8
  • PDB/RCSB051649