Burton Robert A, Mattila Sampo, Taparowsky Elizabeth J, Post Carol Beth
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907-2091, USA.
Biochemistry. 2006 Aug 15;45(32):9857-65. doi: 10.1021/bi060379n.
B-Myc is an endogenous, N-terminal homologue of transcription factor c-Myc that lacks the C-terminal DNA binding and protein dimerization domain of c-Myc. Clinical mutations in the c-Myc N-terminal region, and the subsequent misregulation of Myc, are implicated in the development of numerous human cancers. Myc functions to both activate and repress transcription by associating with multiple binding partners. We investigated the structural and dynamical properties of B-Myc, free or associated with the transactivation inhibitor, MM-1, and the activator, TBP, using NMR spectroscopy. B-Myc has no persistent tertiary structure, yet regions corresponding to Myc homology boxes 1 and 2 (MBI and MBII, respectively) have molten globule-like characteristics. B-Myc binds to MM-1 in a specific manner without becoming highly structured. The local regions of B-Myc involved in binding differ for MM-1 and TBP, and regions not identified by mutagenesis are found to be involved in MM-1 binding. The results provide new insights into Myc N-terminal protein-protein interactions. We propose a model for Myc regulation through differential involvement of MBI and MBII in the binding of Myc interacting proteins.
B-Myc是转录因子c-Myc的内源性N端同源物，它缺乏c-Myc的C端DNA结合和蛋白质二聚化结构域。c-Myc N端区域的临床突变以及随后Myc的调控异常与多种人类癌症的发生有关。Myc通过与多个结合伙伴相互作用来激活和抑制转录。我们使用核磁共振光谱研究了游离的或与反式激活抑制剂MM-1以及激活剂TBP结合的B-Myc的结构和动力学特性。B-Myc没有持久的三级结构，然而对应于Myc同源框1和2（分别为MBI和MBII）的区域具有类熔球的特征。B-Myc以特定方式与MM-1结合，且不会形成高度结构化。B-Myc中参与与MM-1和TBP结合的局部区域不同，并且通过诱变未鉴定出的区域被发现参与与MM-1的结合。这些结果为Myc N端蛋白质-蛋白质相互作用提供了新的见解。我们提出了一个通过MBI和MBII在Myc相互作用蛋白结合中的不同参与来调控Myc的模型。
