Huang Ying, Fang Jia, Bedford Mark T, Zhang Yi, Xu Rui-Ming
W. M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Science. 2006 May 5;312(5774):748-51. doi: 10.1126/science.1125162. Epub 2006 Apr 6.
Biological responses to histone methylation critically depend on the faithful readout and transduction of the methyl-lysine signal by "effector" proteins, yet our understanding of methyl-lysine recognition has so far been limited to the study of histone binding by chromodomain and WD40-repeat proteins. The double tudor domain of JMJD2A, a Jmjc domain-containing histone demethylase, binds methylated histone H3-K4 and H4-K20. We found that the double tudor domain has an interdigitated structure, and the unusual fold is required for its ability to bind methylated histone tails. The cocrystal structure of the JMJD2A double tudor domain with a trimethylated H3-K4 peptide reveals that the trimethyl-K4 is bound in a cage of three aromatic residues, two of which are from the tudor-2 motif, whereas the binding specificity is determined by side-chain interactions involving amino acids from the tudor-1 motif. Our study provides mechanistic insights into recognition of methylated histone tails by tudor domains and reveals the structural intricacy of methyl-lysine recognition by two closely spaced effector domains.
对组蛋白甲基化的生物学反应关键取决于“效应器”蛋白对甲基赖氨酸信号的准确读取和转导，然而到目前为止，我们对甲基赖氨酸识别的理解仅限于对含色域和WD40重复蛋白与组蛋白结合的研究。含Jmjc结构域的组蛋白去甲基化酶JMJD2A的双 Tudor结构域可结合甲基化的组蛋白H3-K4和H4-K20。我们发现双 Tudor结构域具有相互交错的结构，这种不同寻常的折叠结构是其结合甲基化组蛋白尾部能力所必需的。JMJD2A双 Tudor结构域与三甲基化H3-K4肽的共晶体结构表明，三甲基-K4被束缚在由三个芳香族残基构成的笼状结构中，其中两个来自Tudor-2基序，而结合特异性则由涉及Tudor-1基序氨基酸的侧链相互作用决定。我们的研究为Tudor结构域识别甲基化组蛋白尾部提供了机制上的见解，并揭示了两个紧密相邻的效应器结构域识别甲基赖氨酸的结构复杂性。
