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首页> 外文期刊>Biochemistry >Thermodynamic Characterization of the Binding Interaction between the Histone Demethylase LSD1/KDM1 and CoREST
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Thermodynamic Characterization of the Binding Interaction between the Histone Demethylase LSD1/KDM1 and CoREST

机译：组蛋白脱甲基酶LSD1 / KDM1与CoREST之间的结合相互作用的热力学表征

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Flavin-dependent histone demethylases catalyze the posttranslational oxidative demethylation of mono- and dimethylated lysine residues, producing formaldehyde and hydrogen peroxide in addition to the corresponding demethylated protein. In vivo, histone demethylase LSD1 (KDM1; BCH110) is a component of the multiprotein complex that includes histone deacetylases (HDAC 1 and 2) and the scaffolding protein CoREST. Although little is known about the affinities of or the structural basis for the interaction between CoREST and HDACs, the structure of CoREST~(286-482) bound to an a-helical coiled-coil tower domain within LSD1 has recently been reported. Given the significance of CoREST in directing demethylation to specific nucleosomal substrates, insight into the molecular basis of the interaction between CoREST and LSD1 may suggest a new means of inhibiting LSD1 activity by misdirecting the enzyme away from nucleosomal substrates. Toward this end, isothermal titration calorimetry studies were conducted to determine the affinity and thermodynamic parameters characterizing the binding interaction between LSD1 and CoREST~(286-482). The proteins tightly interact in a 1:1 stoichiometry with a dissociation constant (K_d) of 15.9 ±- 2.07 nM, and their binding interaction is characterized by a favorable enthalpic contribution near room temperature with a smaller entropic penalty at pH 7.4. Additionally, one proton is transferred from the buffer to the heterodimeric complex at pH 7.4. From the temperature dependence of the enthalpy change of interaction, a constant-pressure heat capacity change (ΔC_p) of the interaction was determined to be -0.80 ±- 0.01 kcal mol~(-1) K~(-1). Notably, structure-driven truncation of CoREST revealed that the central binding determinant lies within the segment of residues 293-380, also known as the CoREST "linker" region, which is a central isolated helix that interacts with the LSD1 coiled-coil tower domain to create a triple-helical bundle. Thermodynamic parameters obtained from the binding between LSD1 and the linker region of CoREST are similar to those obtained from the interaction between LSD1 and CoREST~(286-482). These results provide a framework for understanding the molecular basis of protein-protein interactions that govern nucleosomal demethylation.
机译：黄素依赖性组蛋白脱甲基酶催化单和二甲基赖氨酸残基的翻译后氧化脱甲基，除相应的脱甲基蛋白外，还产生甲醛和过氧化氢。在体内，组蛋白脱甲基酶LSD1（KDM1; BCH110）是包含组蛋白脱乙酰基酶（HDAC 1和2）和支架蛋白CoREST的多蛋白复合物的组成部分。尽管对CoREST和HDAC之间的亲和力或相互作用的结构基础知之甚少，但最近已报道了与LSD1内的a螺旋螺旋线圈塔结构域结合的CoREST_（286-482）的结构。鉴于CoREST在指导去甲基化至特定的核小体底物方面的重要性，深入了解CoREST与LSD1之间相互作用的分子基础可能表明了一种通过将酶从核小体底物上错位而抑制LSD1活性的新方法。为此，进行了等温滴定量热法研究，以确定表征LSD1与CoREST〜（286-482）之间结合相互作用的亲和力和热力学参数。蛋白质以1：1的化学计量比紧密相互作用，解离常数（K_d）为15.9±-2.07 nM，其结合相互作用的特征是在室温附近具有有利的焓贡献，在pH 7.4时熵熵较小。另外，一个质子在pH 7.4下从缓冲液转移到异二聚体复合物。根据相互作用的焓变的温度依赖性，确定相互作用的恒压热容变化（ΔC_p）为-0.80±-0.01kcal mol〜（-1）K〜（-1）。值得注意的是，CoREST的结构驱动截短揭示了中央结合决定簇位于残基293-380的片段内，也称为CoREST“连接子”区域，该区域是与LSD1螺旋线圈塔结构域相互作用的中央孤立螺旋。创建一个三螺旋束。从LSD1和CoREST的连接子区域之间的结合获得的热力学参数类似于从LSD1和CoREST_（286-482）的相互作用获得的热力学参数。这些结果提供了一个框架，用于理解控制核小体去甲基化的蛋白质-蛋白质相互作用的分子基础。

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