Structural Basis of RACK7 PHD Domain to Read a Pediatric Glioblastoma-Associated Histone Mutation H3.3G34R
Structural Basis of RACK7 PHD Domain to Read a Pediatric Glioblastoma-Associated Histone Mutation H3.3G34R
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RACK7 PHD 结构域读取儿童胶质母细胞瘤相关组蛋白突变 H3.3G34R 的结构基础
DOI：
10.1002/cjoc.202100277
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发表时间：
2021-07-01
影响因子：
5.4
通讯作者：
Cao, Chunyang
中科院分区：
文献类型：
--
作者：
Lan, Wenxian;Li, Ze;Cao, Chunyang
主要观察结果和结论组蛋白H3基因27位（K27 M）、34位（G34 R/V、G34 W、G34 L）和36位（K36 M）的错义突变被鉴定为潜在的癌症驱动突变。H3.3G34R/V突变导致儿童胶质母细胞瘤（GBM）。RACK7（也称为ZMYND 8，PRKCBP 1）最近被报道通过其PHD（plant homedomain）结构域（PHDRACK7）在体外和在H3. 3G34R小儿胶质母细胞瘤细胞中特异性结合H3. 3G34R，在H3. 3G34R介导的基因转录中起关键作用。在此，我们提供了生化和NMR结构证据，PHDRACK7识别组蛋白H3.3G34R突变体通过一种不同于所有其他已报道的PHD结构域的机制。除已报道的D104残基外，还发现了PHDRACK7与组蛋白H3.3G34R肽段相互作用所必需的两个新位点D108和L121。我们的研究结果为H3.3G34R突变驱动的儿童GBM提供了潜在的分子基础。
Main observation and conclusion Histone point mutations, including missense mutations on histone H3 at positions 27 (K27M), 34 (G34R/V, G34W, G34L) and 36 (K36M), were identified as potential cancer driver mutations. H3.3G34R/V mutations account for pediatric glioblastomas (GBM). RACK7 (also known as ZMYND8, PRKCBP1) was recently reported to specifically bind H3.3G34R through its PHD (plant homedomain) domain (PHDRACK7) in vitro and in H3.3G34R pediatric glioblastoma cells, playing key roles in H3.3G34R-mediated gene transcription. Herein, we provided both biochemical and NMR structural evidences that PHDRACK7 recognized histone H3.3G34R mutant via a mechanism distinct from all other reported PHD domains. Except the reported residue D104, two new sites D108 and L121 of PHDRACK7 were found necessary for the interactions between PHDRACK7 and histone H3.3G34R peptide. Our results provided a potential molecular basis for pediatric GBM driven by the H3.3G34R mutation.