A ligand-activated nuclear localization signal in cellular retinoic acid binding protein-II

Mol Cell. 2005 Apr 29;18(3):343-53. doi: 10.1016/j.molcel.2005.03.026.


Primary sequences of proteins often contain motifs that serve as "signatures" for subcellular targeting, such as a nuclear localization signal (NLS). However, many nuclear proteins do not harbor a recognizable NLS, and the pathways that mediate their nuclear translocation are unknown. This work focuses on CRABP-II, a cytosolic protein that moves to the nucleus upon binding of retinoic acid. While CRABP-II does not contain an NLS in its primary sequence, such a motif could be recognized in the protein's tertiary structure. We map the retinoic acid-induced structural rearrangements that result in the presence of this NLS in holo- but not apo-CRABP-II. The signal, whose three-dimensional configuration aligns strikingly well with a "classical" NLS, mediates ligand-induced association of CRABP-II with importin alpha and is critical for nuclear localization of the protein. The ligand-controlled NLS "switch" of CRABP-II may represent a general mechanism for posttranslational regulation of the subcellular distribution of a protein.

Publication types

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

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Cell Nucleus / metabolism
  • Gene Expression Regulation
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Nuclear Localization Signals*
  • Protein Structure, Tertiary
  • Receptors, Retinoic Acid / chemistry
  • Receptors, Retinoic Acid / genetics*
  • Receptors, Retinoic Acid / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Tretinoin / metabolism
  • alpha Karyopherins / metabolism


  • Ligands
  • Nuclear Localization Signals
  • Receptors, Retinoic Acid
  • Recombinant Fusion Proteins
  • alpha Karyopherins
  • retinoic acid binding protein II, cellular
  • Tretinoin