Flexible and Extended Linker Domains Support Efficient Targeting of Heh2 to the Inner Nuclear Membrane

Structure. 2020 Feb 4;28(2):185-195.e5. doi: 10.1016/j.str.2019.11.003. Epub 2019 Dec 2.

Abstract

The nuclear pore complex (NPC) is embedded in the nuclear envelope and forms the main gateway to the nuclear interior including the inner nuclear membrane (INM). Two INM proteins in yeast are selectively imported. Their sorting signals consist of a nuclear localization signal, separated from the transmembrane domain by a long intrinsically disordered (ID) linker. We used computational models to predict the dynamic conformations of ID linkers and analyzed the INM targeting efficiency of proteins with linker regions with altered Stokes radii and decreased flexibilities. We find that flexibility, Stokes radius, and the frequency at which the linkers are at an extended end-to-end distance larger than 25 nm are good predictors for the targeting of the proteins. The data are consistent with a transport mechanism in which INM targeting of Heh2 is dependent on an ID linker that facilitates the crossing of the approximately 25-nm thick NPC scaffold.

Keywords: Saccharomyces cerevisiae; intrinsically disordered domain; membrane protein; nuclear pore complex; nuclear transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Models, Molecular
  • Mutation
  • Nuclear Envelope / metabolism*
  • Nuclear Proteins / chemistry*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Conformation
  • Protein Domains
  • Protein Sorting Signals
  • Protein Unfolding
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*

Substances

  • Heh2 protein, S cerevisiae
  • Membrane Proteins
  • Nuclear Proteins
  • Protein Sorting Signals