Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA.
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Cell Rep. 2018 Mar 20;22(12):3251-3264. doi: 10.1016/j.celrep.2018.02.097.
Transcription activation domains (ADs) are inherently disordered proteins that often target multiple coactivator complexes, but the specificity of these interactions is not understood. Efficient transcription activation by yeast Gcn4 requires its tandem ADs and four activator-binding domains (ABDs) on its target, the Mediator subunit Med15. Multiple ABDs are a common feature of coactivator complexes. We find that the large Gcn4-Med15 complex is heterogeneous and contains nearly all possible AD-ABD interactions. Gcn4-Med15 forms via a dynamic fuzzy protein-protein interface, where ADs bind the ABDs in multiple orientations via hydrophobic regions that gain helicity. This combinatorial mechanism allows individual low-affinity and specificity interactions to generate a biologically functional, specific, and higher affinity complex despite lacking a defined protein-protein interface. This binding strategy is likely representative of many activators that target multiple coactivators, as it allows great flexibility in combinations of activators that can cooperate to regulate genes with variable coactivator requirements.
转录激活结构域（AD）是天然无序的蛋白质，通常靶向多个共激活因子复合物，但这些相互作用的特异性尚不清楚。酵母 Gcn4 的有效转录激活需要其串联 AD 和其靶标 Mediator 亚基 Med15 上的四个激活剂结合结构域（ABD）。多个 ABD 是共激活因子复合物的常见特征。我们发现，大型 Gcn4-Med15 复合物是异质的，包含几乎所有可能的 AD-ABD 相互作用。Gcn4-Med15 通过动态模糊的蛋白质-蛋白质界面形成，其中 AD 通过获得螺旋性的疏水区以多种取向结合 ABD。这种组合机制允许单个低亲和力和特异性相互作用产生具有生物学功能、特异性和更高亲和力的复合物，尽管缺乏明确的蛋白质-蛋白质界面。尽管缺乏明确的蛋白质-蛋白质界面，但这种结合策略可能代表了许多靶向多个共激活因子的激活因子，因为它允许在可以合作调节具有可变共激活因子要求的基因的激活因子的组合中具有很大的灵活性。
