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 language | English |
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Pages (from-to) | 1130-45 |
Number of pages | 16 |
Journal | Cell |
Volume | 157 |
Issue number | 5 |
DOIs | |
Publication status | Published - 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