Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.
Thermodynamic characterization of the binding interaction between the histone demethylase LSD1/KDM1 and CoREST.
复制标题
组蛋白去甲基酶 LSD1/KDM1 与 CoREST 之间结合相互作用的热力学表征。
DOI：
10.1021/bi101776t
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发表时间：
2011-02-01
期刊：
影响因子：
2.9
通讯作者：
McCafferty DG
中科院分区：
文献类型：
--
作者：
Hwang S;Schmitt AA;Luteran AE;Toone EJ;McCafferty DG
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, the histone demethylase LSD1 (KDM1; BCH110) is a component of the multiprotein complex that includes histone deacetylases (HDACs 1/2) and the scaffolding protein CoREST. Although little is known concerning the affinities of or the structural basis for the interaction between CoREST and HDACs, the structure of CoREST286–482 bound to an alpha helical coiled-coil tower domain within LSD1 has been recently 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 to inhibit LSD1 activity by misdirecting the enzyme away from nucleosomal substrates. Towards this end, isothermal titration calorimetry studies (ITC) were conducted to determine the affinity and thermodynamic parameters characterizing the binding interaction between LSD1 and CoREST286–482. The proteins tightly interact in a 1:1 stoichiometry with a dissociation constant (Kd) 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 (ΔCp) of the interaction was determined to be −0.80 ± 0.01 kcal/mol·K. Notably, structure-driven truncation of CoREST revealed that the central binding determinant lies within 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 region293–380 of CoREST are similar to those obtained from the interaction between LSD1 and CoREST286–482. These results provide a framework for understanding the molecular basis of protein-protein interactions that govern nucleosomal demethylation.
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