NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.
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.
Max-Planck-Institut für Biophysikalische Chemie, Göttingen, Germany.
Thomas
T
Güttler
Tobias
T
Madl
Piotr
P
Neumann
Danilo
D
Deichsel
Lorenzo
L
Corsini
Thomas
T
Monecke
Ralf
R
Ficner
Michael
M
Sattler
Dirk
D
Görlich
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D001665:Binding Sites; D016384:Consensus Sequence; D018360:Crystallography, X-Ray; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D028884:Karyopherins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D049790:Nuclear Export Signals; D019906:Nuclear Magnetic Resonance, Biomolecular; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics; D020931:ran GTP-Binding Protein / Q000737:chemistry*; D054321:rev Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism; D000097606:Exportin 1 Protein
D047908:Intracellular Signaling Peptides and Proteins; D028884:Karyopherins; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D020931:ran GTP-Binding Protein; D054321:rev Gene Products, Human Immunodeficiency Virus; D000097606:Exportin 1 Protein; C015482:protein kinase modulator; C514860:rev protein, Human Immunodeficiency Virus-1