Structure of the exportin Xpo4 in complex with RanGTP and the hypusine-containing translation factor eIF5A

Nat Commun. 2016 Jun 16:7:11952. doi: 10.1038/ncomms11952.

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