Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth College, Hanover, NH, United States of America.
Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States of America.
PLoS One. 2019 Dec 2;14(12):e0225784. doi: 10.1371/journal.pone.0225784. eCollection 2019.
Our primary goal is to therapeutically target the oncogenic transcription factor MYC to stop tumor growth and cancer progression. Here, we report aspects of the biophysical states of the MYC protein and its interaction with one of the best-characterized MYC cofactors, TRansactivation/tRansformation-domain Associated Protein (TRRAP). The MYC:TRRAP interaction is critical for MYC function in promoting cancer. The interaction between MYC and TRRAP occurs at a precise region in the MYC protein, called MYC Homology Box 2 (MB2), which is central to the MYC transactivation domain (TAD). Although the MYC TAD is inherently disordered, this report suggests that MB2 may acquire a defined structure when complexed with TRRAP which could be exploited for the investigation of inhibitors of MYC function by preventing this protein-protein interaction (PPI). The MYC TAD, and in particular the MB2 motif, is unique and invariant in evolution, suggesting that MB2 is an ideal site for inhibiting MYC function.
我们的主要目标是通过治疗靶向致癌转录因子 MYC 来阻止肿瘤生长和癌症进展。在这里，我们报告了 MYC 蛋白及其与最具特征性的 MYC 共因子之一——转导/转化结构域相关蛋白（TRansactivation/tRansformation-domain Associated Protein，TRRAP）相互作用的生物物理状态的各个方面。MYC:TRRAP 相互作用对于 MYC 促进癌症的功能至关重要。MYC 和 TRRAP 之间的相互作用发生在 MYC 蛋白的一个精确区域，称为 MYC 同源盒 2（MYC Homology Box 2，MB2），这是 MYC 反式激活结构域（Transactivation Domain，TAD）的核心。尽管 MYC TAD 本质上是无定形的，但本报告表明，当与 TRRAP 形成复合物时，MB2 可能获得明确的结构，这可以通过阻止这种蛋白质-蛋白质相互作用（Protein-Protein Interaction，PPI）来研究抑制 MYC 功能的抑制剂来加以利用。MYC TAD，特别是 MB2 基序，在进化中是独特且不变的，这表明 MB2 是抑制 MYC 功能的理想部位。
