Nielsen Peter R, Nietlispach Daniel, Mott Helen R, Callaghan Juliana, Bannister Andrew, Kouzarides Tony, Murzin Alexey G, Murzina Natalia V, Laue Ernest D
Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Nature. 2002 Mar 7;416(6876):103-7. doi: 10.1038/nature722. Epub 2002 Feb 20.
Specific modifications to histones are essential epigenetic markers---heritable changes in gene expression that do not affect the DNA sequence. Methylation of lysine 9 in histone H3 is recognized by heterochromatin protein 1 (HP1), which directs the binding of other proteins to control chromatin structure and gene expression. Here we show that HP1 uses an induced-fit mechanism for recognition of this modification, as revealed by the structure of its chromodomain bound to a histone H3 peptide dimethylated at Nzeta of lysine 9. The binding pocket for the N-methyl groups is provided by three aromatic side chains, Tyr21, Trp42 and Phe45, which reside in two regions that become ordered on binding of the peptide. The side chain of Lys9 is almost fully extended and surrounded by residues that are conserved in many other chromodomains. The QTAR peptide sequence preceding Lys9 makes most of the additional interactions with the chromodomain, with HP1 residues Val23, Leu40, Trp42, Leu58 and Cys60 appearing to be a major determinant of specificity by binding the key buried Ala7. These findings predict which other chromodomains will bind methylated proteins and suggest a motif that they recognize.
组蛋白的特定修饰是至关重要的表观遗传标记——即基因表达中的可遗传变化,这些变化不影响DNA序列。组蛋白H3赖氨酸9的甲基化可被异染色质蛋白1(HP1)识别,HP1引导其他蛋白质结合以控制染色质结构和基因表达。在此我们表明,HP1采用诱导契合机制来识别这种修饰,这是由其色域与赖氨酸9的Nzeta位二甲基化的组蛋白H3肽结合的结构所揭示的。N-甲基基团的结合口袋由三个芳香族侧链Tyr21、Trp42和Phe45提供,它们位于肽结合时变得有序的两个区域。赖氨酸9的侧链几乎完全伸展,并被许多其他色域中保守的残基所包围。赖氨酸9之前的QTAR肽序列与色域形成了大部分额外的相互作用,HP1残基Val23、Leu40、Trp42、Leu58和Cys60似乎通过结合关键的埋藏Ala7而成为特异性的主要决定因素。这些发现预测了哪些其他色域将结合甲基化蛋白,并提出了它们所识别的基序。