The molecular basis of allostery in a facilitated dissociation process.
The molecular basis of allostery in a facilitated dissociation process.
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易化解离过程中变构的分子基础。
DOI：
10.1016/j.str.2021.07.011
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发表时间：
2021-12-02
期刊：
影响因子：
--
通讯作者：
Wright PE
中科院分区：
文献类型：
--
作者：
Appling FD;Berlow RB;Stanfield RL;Dyson HJ;Wright PE
促进解离提供了一种机制，通过这种机制，高亲和力复合物可以快速分解。负反馈调节因子CITED 2通过从转录辅激活因子CBP和p300的TAZ 1结构域置换缺氧诱导转录因子HIF-1α，有效地下调缺氧反应。置换通过易化解离机制发生，该机制涉及通过内在无序的CITED 2激活结构域与TAZ 1：HIF-1α复合物结合形成的瞬时三元中间体。中间体的短寿命排除了直接的结构研究。为了深入了解易化解离的分子决定因素，我们通过生成由主要CITED 2和HIF-1α结合基序组成的融合肽来模拟三元中间体。融合肽复合物的X射线晶体学和NMR研究揭示了TAZ 1介导的负协同性，其导致特异性CITED 2和HIF-1α相互作用基序几乎相互排斥的结合，为终止缺氧反应的变构开关提供了分子水平的见解。缺氧的转录反应受一对无序蛋白HIF-1α和CITED 2的调节。CITED 2通过易化解离竞争共享分子靶点下调HIF-1α介导的转录。Appling等人使用由HIF-1α和CITED 2结合基序组成的融合肽模拟了该过程的中间体。
Facilitated dissociation provides a mechanism by which high-affinity complexes can be rapidly disassembled. The negative feedback regulator CITED2 efficiently downregulates the hypoxic response by displacing the hypoxia inducible transcription factor HIF-1α from the TAZ1 domain of the transcriptional coactivators CBP and p300. Displacement occurs by a facilitated dissociation mechanism involving a transient ternary intermediate formed by binding of the intrinsically disordered CITED2 activation domain to the TAZ1:HIF-1α complex. The short lifetime of the intermediate precludes straightforward structural investigations. To obtain insights into the molecular determinants of facilitated dissociation, we model the ternary intermediate by generating a fusion peptide composed of the primary CITED2 and HIF-1α binding motifs. X-ray crystallographic and NMR studies of the fusion peptide complex reveal TAZ1-mediated negative cooperativity that results in nearly mutually exclusive binding of specific CITED2 and HIF-1α interaction motifs, providing molecular level insights into the allosteric switch that terminates the hypoxic response. The transcriptional response to hypoxia is regulated by a pair of disordered proteins, HIF-1α and CITED2. CITED2 downregulates HIF-1α-mediated transcription by competing for a shared molecular target by facilitated dissociation. Appling et al. model the intermediate of this process using a fusion peptide comprised of HIF-1α and CITED2 binding motifs.
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影响因子：
56.9
作者：
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通讯作者：
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DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
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