Abstract
Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology*
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Binding Sites
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Consensus Sequence
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Crystallography, X-Ray
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Exportin 1 Protein
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / metabolism
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Karyopherins / chemistry*
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Karyopherins / genetics
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Models, Molecular
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Molecular Sequence Data
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Nuclear Export Signals*
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Nuclear Magnetic Resonance, Biomolecular
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Point Mutation
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Protein Structure, Tertiary
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Receptors, Cytoplasmic and Nuclear / chemistry*
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Receptors, Cytoplasmic and Nuclear / genetics
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ran GTP-Binding Protein / chemistry*
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rev Gene Products, Human Immunodeficiency Virus / chemistry
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rev Gene Products, Human Immunodeficiency Virus / metabolism
Substances
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Intracellular Signaling Peptides and Proteins
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Karyopherins
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Nuclear Export Signals
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Receptors, Cytoplasmic and Nuclear
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protein kinase modulator
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rev Gene Products, Human Immunodeficiency Virus
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rev protein, Human Immunodeficiency Virus-1
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ran GTP-Binding Protein
Associated data
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PDB/3NBY
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PDB/3NBZ
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PDB/3NC0
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PDB/3NC1