Distinctive Properties of the Nuclear Localization Signals of Inner Nuclear Membrane Proteins Heh1 and Heh2

Structure. 2015 Jul 7;23(7):1305-1316. doi: 10.1016/j.str.2015.04.017. Epub 2015 Jun 4.


Targeting of ER-synthesized membrane proteins to the inner nuclear membrane (INM) has long been explained by the diffusion-retention model. However, several INM proteins contain non-classical nuclear localization signal (NLS) sequences, which, in a few instances, have been shown to promote importin α/β- and Ran-dependent translocation to the INM. Here, using structural and biochemical methods, we show that yeast INM proteins Heh2 and Src1/Heh1 contain bipartite import sequences that associate intimately with the minor NLS-binding pocket of yeast importin α and unlike classical NLSs efficiently displace the IBB domain in the absence of importin β. In vivo, the intimate interactions at the minor NLS-binding pocket make the h2NLS highly efficient at recruiting importin α at the ER and drive INM localization of endogenous Heh2. Thus, h1/h2NLSs delineate a novel class of super-potent, IBB-like membrane protein NLSs, distinct from classical NLSs found in soluble cargos and of general interest in biology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Binding Sites
  • Endoplasmic Reticulum / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Molecular Sequence Data
  • Nuclear Envelope
  • Nuclear Localization Signals
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism*
  • beta Karyopherins / metabolism


  • Heh2 protein, S cerevisiae
  • Membrane Proteins
  • Nuclear Localization Signals
  • Nuclear Proteins
  • Saccharomyces cerevisiae Proteins
  • Src1 protein, S cerevisiae
  • beta Karyopherins

Associated data

  • PDB/4PVZ
  • PDB/4XZR