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

• Published in: Cell Vol. 157; no. 5; pp. 1130 - 1145
• Main Authors: Lu, Min, Zak, Jaroslav, Chen, Shuo, Sanchez-Pulido, Luis, Severson, David T., Endicott, Jane, Ponting, Chris P., Schofield, Christopher J., Lu, Xin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.05.2014
• Subjects: Active Transport, Cell Nucleus; Ankyrin Repeat; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Humans; Models, Molecular; Multiprotein Complexes - metabolism; Protein Transport; Proteins - chemistry; Proteins - metabolism; ran GTP-Binding Protein - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2014.05.006

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. [Display omitted] •RanGDP binding to ankyrin repeat (AR) defines the RaDAR nuclear import pathway•Hydrophobic 13th residues in ARs (AR13Hb) form a code for RanGDP binding•The most common familial melanoma CDKN2A mutation introduces the code into the p16•Presence of AR13Hb in two consecutive ARs predicts the nuclear localization of ARPs Ankyrin-repeat-containing proteins, including transcriptional regulators of NF-κB and p53, use patterned binding of RanGDP within their ankyrin repeats to regulate their nuclear localization independent of the importin pathway.