Abstract
Xpo4 is a bidirectional nuclear transport receptor that mediates nuclear export of eIF5A and Smad3 as well as import of Sox2 and SRY. How Xpo4 recognizes such a variety of cargoes is as yet unknown. Here we present the crystal structure of the RanGTP·Xpo4·eIF5A export complex at 3.2 Å resolution. Xpo4 has a similar structure as CRM1, but the NES-binding site is occluded, and a new interaction site evolved that recognizes both globular domains of eIF5A. eIF5A contains hypusine, a unique amino acid with two positive charges, which is essential for cell viability and eIF5A function in translation. The hypusine docks into a deep, acidic pocket of Xpo4 and is thus a critical element of eIF5A's complex export signature. This further suggests that Xpo4 recognizes other cargoes differently, and illustrates how Xpo4 suppresses - in a chaperone-like manner - undesired interactions of eIF5A inside nuclei.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Sequence
-
Binding Sites
-
Cloning, Molecular
-
Crystallography, X-Ray
-
Escherichia coli / genetics
-
Escherichia coli / metabolism
-
Eukaryotic Translation Initiation Factor 5A
-
Gene Expression
-
Genetic Vectors / chemistry
-
Genetic Vectors / metabolism
-
Humans
-
Karyopherins / chemistry*
-
Karyopherins / genetics
-
Karyopherins / metabolism
-
Kinetics
-
Lysine / analogs & derivatives*
-
Lysine / chemistry
-
Lysine / metabolism
-
Molecular Docking Simulation
-
Peptide Initiation Factors / chemistry*
-
Peptide Initiation Factors / genetics
-
Peptide Initiation Factors / metabolism
-
Protein Binding
-
Protein Conformation, alpha-Helical
-
Protein Conformation, beta-Strand
-
Protein Interaction Domains and Motifs
-
RNA-Binding Proteins / chemistry*
-
RNA-Binding Proteins / genetics
-
RNA-Binding Proteins / metabolism
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / genetics
-
Recombinant Proteins / metabolism
-
Sequence Alignment
-
Sequence Homology, Amino Acid
-
Thermodynamics
-
ran GTP-Binding Protein / chemistry*
-
ran GTP-Binding Protein / genetics
-
ran GTP-Binding Protein / metabolism
Substances
-
Karyopherins
-
Peptide Initiation Factors
-
RAN protein, human
-
RNA-Binding Proteins
-
Recombinant Proteins
-
Xpo4 protein, human
-
hypusine
-
ran GTP-Binding Protein
-
Lysine