Nair Satish K, Burley Stephen K
Laboratories of Molecular Biophysics, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Cell. 2003 Jan 24;112(2):193-205. doi: 10.1016/s0092-8674(02)01284-9.
X-ray structures of the basic/helix-loop-helix/leucine zipper (bHLHZ) domains of Myc-Max and Mad-Max heterodimers bound to their common DNA target (Enhancer or E box hexanucleotide, 5'-CACGTG-3') have been determined at 1.9 A and 2.0 A resolution, respectively. E box recognition by these two structurally similar transcription factor pairs determines whether a cell will divide and proliferate (Myc-Max) or differentiate and become quiescent (Mad-Max). Deregulation of Myc has been implicated in the development of many human cancers, including Burkitt's lymphoma, neuroblastomas, and small cell lung cancers. Both quasisymmetric heterodimers resemble the symmetric Max homodimer, albeit with marked structural differences in the coiled-coil leucine zipper regions that explain preferential homo- and heteromeric dimerization of these three evolutionarily related DNA-binding proteins. The Myc-Max heterodimer, but not its Mad-Max counterpart, dimerizes to form a bivalent heterotetramer, which explains how Myc can upregulate expression of genes with promoters bearing widely separated E boxes.
Myc-Max和Mad-Max异二聚体的碱性/螺旋-环-螺旋/亮氨酸拉链（bHLHZ）结构域与它们共同的DNA靶标（增强子或E盒六核苷酸，5'-CACGTG-3'）结合的X射线结构分别在1.9埃和2.0埃分辨率下被确定。这两对结构相似的转录因子对E盒的识别决定了细胞是会分裂和增殖（Myc-Max）还是分化并进入静止状态（Mad-Max）。Myc的失调与许多人类癌症的发生有关，包括伯基特淋巴瘤、神经母细胞瘤和小细胞肺癌。这两种准对称异二聚体都类似于对称的Max同二聚体，尽管在卷曲螺旋亮氨酸拉链区域存在明显的结构差异，这解释了这三种进化相关的DNA结合蛋白优先形成同源和异源二聚体的原因。Myc-Max异二聚体，而不是其Mad-Max对应物，二聚化形成二价异源四聚体，这解释了Myc如何上调具有间隔广泛的E盒启动子的基因的表达。
