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

Carlo Petosa; Guy Schoehn; Peter Askjaer; Ulrike Bauer; Martine Moulin; Ulrich Steuerwald; Montserrat Soler-López; Florence Baudin; Iain W Mattaj; Christoph W Müller

doi:10.1016/j.molcel.2004.11.018

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.

Authors

Carlo Petosa¹, Guy Schoehn, Peter Askjaer, Ulrike Bauer, Martine Moulin, Ulrich Steuerwald, Montserrat Soler-López, Florence Baudin, Iain W Mattaj, Christoph W Müller

Affiliation

¹ European Molecular Biology Laboratory, Grenoble Outstation, B.P. 181, 38042 Grenoble Cedex 9, France.

PMID: 15574331
DOI: 10.1016/j.molcel.2004.11.018

Abstract

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
Exportin 1 Protein
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

Substances

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

Associated data

PDB/1W9C