Li P, He X, Gerrero M R, Mok M, Aggarwal A, Rosenfeld M G
Howard Hughes Medical Institute, University of California, School of Medicine, San Diego.
Genes Dev. 1993 Dec;7(12B):2483-96. doi: 10.1101/gad.7.12b.2483.
Investigation of the large POU domain family of developmental regulators has revealed a molecular mechanism by which highly related transcription factors sharing common DNA-binding motifs act to functionally discriminate their cognate DNA sequences. Studies of two classes of neuron-specific POU domain factors (III and IV) indicate that functional specificity on their native response elements is achieved by accommodating different nucleotide spacing between variably oriented bipartite core DNA-binding motifs. The preferred orientation of the POU-specific domain of the neuronal factors on their native response elements appears to be opposite that of Pit-1 and Oct-1. Members of POU-III (Brn-2) class exhibit remarkable flexibility in DNA site recognition (tolerating core motifs spaced by 0, 2, or 3 nucleotides), whereas POU-IV (Brn-3) class is highly constrained (tolerating core motifs with a spacing of 3 nucleotides). The molecular determinant of the constraint in DNA site selection appears to be imparted by 3 amino acid residues in the amino-terminal basic region in concert, with helix 2 of the POU homeo domain which together are involved in minor groove and possibly phosphate backbone contacts. Similar mechanisms may underlie differential flexibility in spacing and orientation for diverse families of transcription factors.
对发育调控因子的大型POU结构域家族的研究揭示了一种分子机制，通过该机制，共享共同DNA结合基序的高度相关转录因子在功能上区分其同源DNA序列。对两类神经元特异性POU结构域因子（III和IV）的研究表明，它们在天然反应元件上的功能特异性是通过适应可变取向的二分核心DNA结合基序之间不同的核苷酸间距来实现的。神经元因子的POU特异性结构域在其天然反应元件上的优选取向似乎与Pit-1和Oct-1相反。POU-III（Brn-2）类成员在DNA位点识别方面表现出显著的灵活性（容忍间隔为0、2或3个核苷酸的核心基序），而POU-IV（Brn-3）类则受到高度限制（容忍间隔为3个核苷酸的核心基序）。DNA位点选择限制的分子决定因素似乎是由氨基末端碱性区域中的3个氨基酸残基与POU同源结构域的螺旋2共同赋予的，它们一起参与小沟以及可能的磷酸骨架接触。类似的机制可能是不同转录因子家族在间距和取向上具有差异灵活性的基础。
