Dong Xiuhua, Biswas Anindita, Süel Katherine E, Jackson Laurie K, Martinez Rita, Gu Hongmei, Chook Yuh Min
Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA.
Nature. 2009 Apr 30;458(7242):1136-41. doi: 10.1038/nature07975. Epub 2009 Apr 1.
CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 A structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined alpha-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.
CRM1（也称为XPO1和输出蛋白1）通过识别富含亮氨酸的核输出信号（LR-NES）介导数百种蛋白质的核输出。在此，我们展示了与核小核糖核蛋白转运蛋白1（SNUPN）结合的CRM1的2.9埃结构。核小核糖核蛋白转运蛋白1通过氨基末端的LR-NES及其核苷酸结合结构域以二分方式结合CRM1。LR-NES是一种组合的α螺旋-延伸结构，占据两个CRM1外部螺旋之间的疏水凹槽。LR-NES界面解释了共有疏水模式、对中间电负性残基的偏好以及对雷帕霉素B的抑制作用。第二个核输出信号表位是核小核糖核蛋白转运蛋白1核苷酸结合结构域上的一个碱性表面，它与CRM1上LR-NES位点相邻的一个酸性区域结合。对单个弱核输出信号表位的多部分识别可能是CRM1底物所共有的，从而增强了CRM1的结合，超出了通常较低亲和力的LR-NES。类似的能量构建也用于多部分核定位信号，以提供广泛的底物特异性和核运输中的快速进化。
