A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway

Min Lu, Jaroslav Zak, Shuo Chen, Luis Sanchez-Pulido, David T Severson, Jane Endicott, Chris P Ponting, Christopher J Schofield, Xin Lu

Research output: Contribution to journalArticlepeer-review

Abstract

Regulation of nuclear import is fundamental to eukaryotic biology. The majority of nuclear import pathways are mediated by importin-cargo interactions. Yet not all nuclear proteins interact with importins, necessitating the identification of a general importin-independent nuclear import pathway. Here, we identify a code that determines importin-independent nuclear import of ankyrin repeats (ARs), a structural motif found in over 250 human proteins with diverse functions. AR-containing proteins (ARPs) with a hydrophobic residue at the 13th position of two consecutive ARs bind RanGDP efficiently, and consequently enter the nucleus. This code, experimentally tested in 17 ARPs, predicts the nuclear-cytoplasmic localization of over 150 annotated human ARPs with high accuracy and is acquired by the most common familial melanoma-associated CDKN2A mutation, leading to nuclear accumulation of mutant p16ink4a. The RaDAR (RanGDP/AR) pathway represents a general importin-independent nuclear import pathway and is frequently used by AR-containing transcriptional regulators, especially those regulating NF-κB/p53.

Original languageEnglish
Pages (from-to)1130-45
Number of pages16
JournalCell
Volume157
Issue number5
DOIs
Publication statusPublished - 22 May 2014

Keywords

  • Active Transport, Cell Nucleus
  • Ankyrin Repeat
  • Cyclin-Dependent Kinase Inhibitor p16
  • Humans
  • Models, Molecular
  • Multiprotein Complexes
  • Protein Transport
  • Proteins
  • ran GTP-Binding Protein

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