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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lu, M; Zak, J; Chen, S; Sanchez-Pulido, L; Severson, DT; Endicott, J; Ponting, CP; Schofield, CJ; Lu, X

Published Date

  • May 2014

Published In

Volume / Issue

  • 157 / 5

Start / End Page

  • 1130 - 1145

PubMed ID

  • 24855949

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

International Standard Serial Number (ISSN)

  • 0092-8674

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2014.05.006

Language

  • eng