Ramirez-Carrozzi Vladimir, Kerppola Tom
Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0650, USA.
Mol Cell Biol. 2003 Mar;23(5):1737-49. doi: 10.1128/MCB.23.5.1737-1749.2003.
Many regulatory elements in eukaryotic promoters do not correspond to optimal recognition sequences for the transcription factors that regulate promoter function by binding to the elements. The sequence of the binding site may influence the structural and functional properties of regulatory protein complexes. Fos-Jun heterodimers were found to bind nonconsensus AP-1 sites in a preferred orientation. Oriented Fos-Jun heterodimer binding was attributed to nonidentical recognition of the two half-sites by Fos and Jun. Jun bound preferentially to the consensus half-site, whereas Fos was able to bind nonconsensus half-sites. The orientation of heterodimer binding affected the transcriptional cooperativity of Fos-Jun-NFAT1 complexes at composite regulatory elements in mammalian cells. Jun dimerization with Fos versus ATF2 caused it to bind opposite half-sites at nonconsensus AP-1 elements. Similarly, ATF2 bound to opposite half-sites in Fos-ATF2-NFAT1 and ATF2-Jun-NFAT1 complexes. The orientations of nonconsensus AP-1 sites within composite regulatory elements affected the cooperativity of Fos-Jun as well as Jun-Jun binding with NFAT1. Since Jun homodimers cannot bind to AP-1 sites in a preferred orientation, the effects of the orientations of nonconsensus AP-1 sites on the stabilities of Jun-Jun-NFAT1 complexes are likely to be due to asymmetric conformational changes in the two subunits of the homodimer. Nonconsensus AP-1 site orientation also affected the synergy of transcription activation between Jun homodimers and NFAT1 at composite regulatory elements. The asymmetric recognition of nonconsensus AP-1 sites can therefore influence the transcriptional activities of Fos and Jun both through effects on the orientation of heterodimer binding and through differential conformational changes in the two subunits of the dimer.
真核生物启动子中的许多调控元件并不对应于通过与这些元件结合来调节启动子功能的转录因子的最佳识别序列。结合位点的序列可能会影响调控蛋白复合物的结构和功能特性。研究发现，Fos-Jun异源二聚体以优先取向结合非共有AP-1位点。Fos-Jun异源二聚体的定向结合归因于Fos和Jun对两个半位点的不同识别。Jun优先结合共有半位点，而Fos能够结合非共有半位点。异源二聚体结合的取向影响了哺乳动物细胞中复合调控元件处Fos-Jun-NFAT1复合物的转录协同性。Jun与Fos而非ATF2二聚化导致其在非共有AP-1元件处结合相反的半位点。同样，ATF2在Fos-ATF2-NFAT1和ATF2-Jun-NFAT1复合物中结合相反的半位点。复合调控元件内非共有AP-1位点的取向影响了Fos-Jun以及Jun-Jun与NFAT1结合的协同性。由于Jun同源二聚体不能以优先取向结合AP-1位点，非共有AP-1位点取向对Jun-Jun-NFAT1复合物稳定性的影响可能是由于同源二聚体两个亚基的不对称构象变化。非共有AP-1位点的取向也影响了复合调控元件处Jun同源二聚体与NFAT1之间转录激活的协同性。因此，非共有AP-1位点的不对称识别既可以通过影响异源二聚体结合的取向，也可以通过二聚体两个亚基的不同构象变化来影响Fos和Jun的转录活性。
