Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta

Mol Cell. 2002 Dec;10(6):1345-53. doi: 10.1016/s1097-2765(02)00727-x.


Nuclear import of proteins containing a classical nuclear localization signal (NLS) involves NLS recognition by importin alpha, which associates with importin beta via the IBB domain. Other proteins, including parathyroid hormone-related protein (PTHrP), are imported into the nucleus by direct interaction with importin beta. We solved the crystal structure of a fragment of importin beta-1 (1-485) bound to the nonclassical NLS of PTHrP. The structure reveals a second extended cargo binding site on importin beta distinct from the IBB domain binding site. Using a permeabilized cell import assay we demonstrate that importin beta (1-485) can import PTHrP-coupled cargo in a Ran-dependent manner. We propose that this region contains a prototypical nuclear import receptor domain, which could have evolved into the modern importin beta superfamily.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / physiology*
  • Amino Acid Sequence
  • Binding Sites
  • Cell Nucleus / metabolism*
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Escherichia coli / genetics
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Parathyroid Hormone-Related Protein
  • Peptide Fragments / chemistry
  • Peptide Hormones / genetics
  • Peptide Hormones / metabolism*
  • Phosphorylation
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Repetitive Sequences, Amino Acid
  • Signal Transduction
  • Static Electricity
  • Surface Properties
  • beta Karyopherins / chemistry
  • beta Karyopherins / metabolism*


  • PTHLH protein, human
  • Parathyroid Hormone-Related Protein
  • Peptide Fragments
  • Peptide Hormones
  • Recombinant Proteins
  • beta Karyopherins

Associated data

  • PDB/1M5N