Evolutionary development of redundant nuclear localization signals in the mRNA export factor NXF1

Mol Biol Cell. 2011 Dec;22(23):4657-68. doi: 10.1091/mbc.E11-03-0222. Epub 2011 Sep 30.


In human cells, the mRNA export factor NXF1 resides in the nucleoplasm and at nuclear pore complexes. Karyopherin β2 or transportin recognizes a proline-tyrosine nuclear localization signal (PY-NLS) in the N-terminal tail of NXF1 and imports it into the nucleus. Here biochemical and cellular studies to understand the energetic organization of the NXF1 PY-NLS reveal unexpected redundancy in the nuclear import pathways used by NXF1. Human NXF1 can be imported via importin β, karyopherin β2, importin 4, importin 11, and importin α. Two NLS epitopes within the N-terminal tail, an N-terminal basic segment and a C-terminal R-X(2-5)-P-Y motif, provide the majority of binding energy for all five karyopherins. Mutation of both NLS epitopes abolishes binding to the karyopherins, mislocalized NXF1 to the cytoplasm, and significantly compromised its mRNA export function. The understanding of how different karyopherins recognize human NXF1, the examination of NXF1 sequences from divergent eukaryotes, and the interactions of NXF1 homologues with various karyopherins reveals the evolutionary development of redundant NLSs in NXF1 of higher eukaryotes. Redundancy of nuclear import pathways for NXF1 increases progressively from fungi to nematodes and insects to chordates, potentially paralleling the increasing complexity in mRNA export regulation and the evolution of new nuclear functions for NXF1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Chordata
  • Cytoplasm / metabolism
  • Epitopes
  • Evolution, Molecular
  • Gene Expression Regulation
  • Helminth Proteins / metabolism
  • Humans
  • Insecta
  • Membrane Transport Proteins / metabolism
  • Mutation
  • Nuclear Localization Signals / physiology*
  • Nucleocytoplasmic Transport Proteins / genetics
  • Nucleocytoplasmic Transport Proteins / immunology
  • Nucleocytoplasmic Transport Proteins / metabolism*
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • RNA-Binding Proteins / metabolism*
  • beta Karyopherins / metabolism


  • Epitopes
  • Helminth Proteins
  • IPO11 protein, human
  • IPO4 protein, human
  • Membrane Transport Proteins
  • NXF1 protein, human
  • Nuclear Localization Signals
  • Nucleocytoplasmic Transport Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • TNPO1 protein, human
  • beta Karyopherins