X-ray structures of Myc-Max and Mad-Max recognizing DNA: Molecular bases of regulation by proto-oncogenic transcription factors
X-ray structures of Myc-Max and Mad-Max recognizing DNA: Molecular bases of regulation by proto-oncogenic transcription factors
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DOI：
10.1016/s0092-8674(02)01284-9
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发表时间：
2003-01-24
期刊：
影响因子：
64.5
通讯作者：
Burley, SK
中科院分区：
文献类型：
--
作者：
Nair, SK;Burley, SK
Myc-Max 和 Mad-Max 异二聚体与其共同 DNA 靶标（增强子或 E 盒六核苷酸，5'-CACGTG-3'）结合的基本/螺旋-环-螺旋/亮氨酸拉链 (bHLHZ) 结构域的 X 射线结构已分别在 1.9 埃和 2.0 埃分辨率下确定。这两个结构相似的转录因子对对 E 盒的识别决定了细胞是否会分裂和增殖 (Myc-Max) 还是分化并变得静止 (Mad-Max)。 Myc 的失调与许多人类癌症的发展有关，包括伯基特淋巴瘤、神经母细胞瘤和小细胞肺癌。两种准对称异二聚体类似于对称 Max 同二聚体，尽管卷曲螺旋亮氨酸拉链区域具有显着的结构差异，这解释了这三种进化相关的 DNA 结合蛋白的优先同聚和异聚二聚化。 Myc-Max 异二聚体（而非其 Mad-Max 对应物）二聚化形成二价异四聚体，这解释了 Myc 如何通过带有广泛分离的 E 盒的启动子上调基因的表达。
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 Angstrom and 2.0 Angstrom 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 quasi-symmetric 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.