title: A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zak
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: Shuo
authors.initials: S
authors.lastname: Chen
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Pulido
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Severson
authors.affiliation: Northern Institute for Cancer Research, University of Newcastle, Newcastle, NE2 4HH, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Endicott
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Ponting
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, OX1 3TA, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schofield
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK. Electronic address: xin.lu@ludwig.ox.ac.uk.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D021581:Active Transport, Cell Nucleus; D017089:Ankyrin Repeat; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000737:chemistry / Q000378:metabolism; D020931:ran GTP-Binding Protein / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D046912:Multiprotein Complexes; D011506:Proteins; D020931:ran GTP-Binding Protein