Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain.
Structural basis for cooperative regulation of KIX-mediated transcription pathways by the HTLV-1 HBZ activation domain.
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HTLV-1 HBZ 激活域协同调节 KIX 介导的转录途径的结构基础。
DOI：
10.1073/pnas.1810397115
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发表时间：
2018
影响因子：
11.1
通讯作者：
Wright,PeterE
中科院分区：
文献类型：
--
作者：
Yang,Ke;Stanfield,RobynL;Martinez-Yamout,MariaA;Dyson,HJane;Wilson,IanA;Wright,PeterE
人类 T 细胞白血病病毒 I 碱性亮氨酸拉链蛋白 (HTLV-1 HBZ) 通过与转录共激活因子 CBP 的 KIX 结构域及其旁系同源物 p300 相互作用的机制知之甚少，维持慢性病毒感染并促进白血病发生。 KIX 结构域在不同的 MLL 和 c-Myb/pKID 位点结合调节蛋白，形成二元或三元复合物。 HBZ 本质上无序的 N 端激活结构域 (HBZ AD) 通过直接与细胞和病毒转录因子竞争与 MLL 位点的结合以及通过变构扰乱造血转录因子 c-Myb 反式激活结构域的结合来解除细胞信号传导通路的调节。三元 KIX:c-Myb:HBZ 复合物的晶体结构表明，HBZ AD 通过串联两亲基序 (L/V)(V/L)DGLL 募集两个 KIX:c-Myb 实体，并在结合后折叠成长 α 螺旋。等温滴定量热法揭示了 c-Myb 激活结构域与 KIX:HBZ 复合物的结合以及 HBZ 与 KIX:c-Myb 复合物的结合具有很强的协同性。此外，KIX 与两个 HBZ (V/L)DGLL 基序的结合是协同的；这些结构表明这种协同性是通过 HBZ α-螺旋在第一个结合基序之外的传播来实现的。我们的研究表明，本质上无序的 HBZ AD 独特的结构灵活性和多重相互作用基序是其劫持 KIX 介导的转录途径的效力的原因。 KIX:c-Myb:HBZ 复合物提供了转录因子：共激活子网络中协同稳定的例子，并深入了解 HBZ 失调造血转录程序并促进 T 细胞增殖的潜在机制。
The human T cell leukemia virus I basic leucine zipper protein (HTLV-1 HBZ) maintains chronic viral infection and promotes leukemogenesis through poorly understood mechanisms involving interactions with the KIX domain of the transcriptional coactivator CBP and its paralog p300. The KIX domain binds regulatory proteins at the distinct MLL and c-Myb/pKID sites to form binary or ternary complexes. The intrinsically disordered N-terminal activation domain of HBZ (HBZ AD) deregulates cellular signaling pathways by competing directly with cellular and viral transcription factors for binding to the MLL site and by allosterically perturbing binding of the transactivation domain of the hematopoietic transcription factor c-Myb. Crystal structures of the ternary KIX:c-Myb:HBZ complex show that the HBZ AD recruits two KIX:c-Myb entities through tandem amphipathic motifs (L/V)(V/L)DGLL and folds into a long α-helix upon binding. Isothermal titration calorimetry reveals strong cooperativity in binding of the c-Myb activation domain to the KIX:HBZ complex and in binding of HBZ to the KIX:c-Myb complex. In addition, binding of KIX to the two HBZ (V/L)DGLL motifs is cooperative; the structures suggest that this cooperativity is achieved through propagation of the HBZ α-helix beyond the first binding motif. Our study suggests that the unique structural flexibility and the multiple interaction motifs of the intrinsically disordered HBZ AD are responsible for its potency in hijacking KIX-mediated transcription pathways. The KIX:c-Myb:HBZ complex provides an example of cooperative stabilization in a transcription factor:coactivator network and gives insights into potential mechanisms through which HBZ dysregulates hematopoietic transcriptional programs and promotes T cell proliferation.