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A Code for RanGDP Binding in Ankyrin Repeats Defines a Nuclear Import Pathway

Lookup NU author(s): Professor Jane Endicott

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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-kappa B/p53.


Publication metadata

Author(s): Lu M, Zak J, Chen SO, Sanchez-Pulido L, Severson DT, Endicott J, Ponting CP, Schofield CJ, Lu X

Publication type: Article

Publication status: Published

Journal: Cell

Year: 2014

Volume: 157

Issue: 5

Pages: 1130-1145

Print publication date: 22/05/2014

ISSN (print): 0092-8674

ISSN (electronic): 1097-4172

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.cell.2014.05.006

DOI: 10.1016/j.cell.2014.05.006


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