Department of Molecular Biology and Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
FEBS Lett. 2010 Nov 19;584(22):4500-4. doi: 10.1016/j.febslet.2010.10.024. Epub 2010 Oct 20.
Physical interaction between the transactivation domain (TAD) of the mixed-lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL-mediated transcriptional activation. We show by alanine-scanning mutagenesis that hydrophobic surface residues of KIX, especially L628, are energetically important for binding the MLL TAD. NMR studies of the KIX-L628A mutant suggest that L628 plays a crucial role in conformational transitions at the MLL binding site, necessary for high affinity interactions with MLL. Unexpectedly, MLL also binds to the c-Myb/phosphorylated kinase-inducible domain of CREB (pKID) site of KIX, highlighting the complex nature of interactions involving intrinsically disordered transcriptional activators.
混合谱系白血病蛋白（MLL）的转录激活结构域（TAD）与环磷酸腺苷反应元件结合蛋白（CREB）结合蛋白（CBP）的 KIX 结构域之间的物理相互作用对于 MLL 介导的转录激活是必需的。我们通过丙氨酸扫描诱变表明，KIX 的疏水面残基，特别是 L628，对于结合 MLL TAD 具有重要的能量意义。对 KIX-L628A 突变体的 NMR 研究表明，L628 在 MLL 结合位点的构象转变中起着至关重要的作用，这对于与 MLL 高亲和力相互作用是必需的。出乎意料的是，MLL 还与 KIX 的 c-Myb/磷酸化激酶诱导结构域（pKID）位点结合，突出了涉及固有无序转录激活物的相互作用的复杂性质。
