Architecture of CRM1/Exportin1 suggests how cooperativity is achieved during formation of a nuclear export complex

Mol Cell. 2004 Dec 3;16(5):761-75. doi: 10.1016/j.molcel.2004.11.018.


CRM1/Exportin1 mediates the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES) by forming a cooperative ternary complex with the NES-bearing substrate and the small GTPase Ran. We present a structural model of human CRM1 based on a combination of X-ray crystallography, homology modeling, and electron microscopy. The architecture of CRM1 resembles that of the import receptor transportin1, with 19 HEAT repeats and a large loop implicated in Ran binding. Residues critical for NES recognition are identified adjacent to the cysteine residue targeted by leptomycin B (LMB), a specific CRM1 inhibitor. We present evidence that a conformational change of the Ran binding loop accounts for the cooperativity of Ran- and substrate binding and for the selective enhancement of CRM1-mediated export by the cofactor RanBP3. Our findings indicate that a single architectural and mechanistic framework can explain the divergent effects of RanGTP on substrate binding by many import and export receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Binding Sites
  • Cell Nucleus / metabolism*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Fatty Acids, Unsaturated / pharmacology
  • GTP Phosphohydrolases / metabolism
  • Guanosine Triphosphate / chemistry
  • Humans
  • Image Processing, Computer-Assisted
  • Karyopherins / chemistry*
  • Karyopherins / metabolism
  • Leucine / chemistry
  • Microscopy, Electron
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear / chemistry*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Sequence Homology, Amino Acid
  • beta Karyopherins / chemistry
  • ran GTP-Binding Protein / metabolism


  • Fatty Acids, Unsaturated
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • TNPO1 protein, human
  • beta Karyopherins
  • exportin 1 protein
  • Guanosine Triphosphate
  • GTP Phosphohydrolases
  • ran GTP-Binding Protein
  • Leucine
  • leptomycin B

Associated data

  • PDB/1W9C