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

作者：Lu Min; Zak Jaroslav; Chen Shuo; Sanchez Pulido Luis; Severson David T; Endicott Jane; Ponting Chris P; Schofield Christopher J; Lu Xin^*

来源：Cell, 2014, 157(5): 1130-1145.

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-kappa B/p53.

• 出版日期2014-5-22