RanGDP 与锚蛋白重复序列的结合密码子定义了核输入途径。

A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway.

机构信息

Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, OX3 7DQ, UK.

MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT, UK.

出版信息

Cell. 2014 May 22;157(5):1130-45. doi: 10.1016/j.cell.2014.05.006.

DOI:10.1016/j.cell.2014.05.006

PMID:24855949

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.

摘要

核输入的调控对真核生物生物学至关重要。大多数核输入途径是通过输入蛋白与货物的相互作用介导的。然而，并非所有核蛋白都与输入蛋白相互作用，这就需要确定一种普遍的不依赖输入蛋白的核输入途径。在这里，我们确定了一个决定锚蛋白重复序列（ARs）不依赖输入蛋白的核输入的密码子，ARs 是一种结构基序，存在于超过 250 种具有不同功能的人类蛋白中。含有两个连续 AR 第 13 位为疏水性残基的 AR 蛋白（ARPs）与 RanGDP 有效结合，从而进入细胞核。该密码子在 17 个 ARP 中进行了实验验证，可高度准确地预测超过 150 种注释的人类 ARP 的核细胞质定位，并且是最常见的家族性黑色素瘤相关 CDKN2A 突变获得的，导致突变型 p16ink4a 核积累。RaDAR（RanGDP/AR）途径代表了一种普遍的不依赖输入蛋白的核输入途径，并且经常被含有 AR 的转录调节剂使用，特别是那些调节 NF-κB/p53 的调节剂。