Huxford T, Huang D B, Malek S, Ghosh G
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla 92093-0359, USA.
Cell. 1998 Dec 11;95(6):759-70. doi: 10.1016/s0092-8674(00)81699-2.
IkappaBalpha regulates the transcription factor NF-kappaB through the formation of stable IkappaBalpha/NF-kappaB complexes. Prior to induction, IkappaBalpha retains NF-kappaB in the cytoplasm until the NF-kappaB activation signal is received. After activation, NF-kappaB is removed from gene promoters through association with nuclear IkappaBalpha, restoring the preinduction state. The 2.3 A crystal structure of IkappaBalpha in complex with the NF-kappaB p50/p65 heterodimer reveals mechanisms of these inhibitory activities. The presence of IkappaBalpha allows large en bloc movement of the NF-kappaB p65 subunit amino-terminal domain. This conformational change induces allosteric inhibition of NF-kappaB DNA binding. Amino acid residues immediately preceding the nuclear localization signals of both NF-kappaB p50 and p65 subunits are tethered to the IkappaBalpha amino-terminal ankyrin repeats, impeding NF-kappaB from nuclear import machinery recognition.
IκBα通过形成稳定的IκBα/NF-κB复合物来调节转录因子NF-κB。在诱导之前，IκBα将NF-κB保留在细胞质中，直到接收到NF-κB激活信号。激活后，NF-κB通过与核IκBα结合而从基因启动子上移除，恢复诱导前状态。IκBα与NF-κB p50/p65异二聚体复合物的2.3埃晶体结构揭示了这些抑制活性的机制。IκBα的存在允许NF-κB p65亚基氨基末端结构域进行大的整体移动。这种构象变化诱导NF-κB DNA结合的变构抑制。NF-κB p50和p65亚基的核定位信号之前紧邻的氨基酸残基与IκBα氨基末端锚蛋白重复序列相连，阻碍NF-κB被核输入机制识别。
