Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders.
Compromised structure and function of HDAC8 mutants identified in Cornelia de Lange Syndrome spectrum disorders.
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DOI：
10.1021/cb5003762
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发表时间：
2014-09-19
影响因子：
4
通讯作者：
Christianson, David W.
中科院分区：
文献类型：
--
作者：
Decroos, Christophe;Bowman, Christine M.;Moser, Joe-Ann S.;Christianson, Karen E.;Deardorff, Matthew A.;Christianson, David W.
Cornelia de Lange综合征(CDLS)是一种多发性先天性异常疾病，其原因是编码粘附素复合体核心成分SMC1A、SMC3和RAD21的基因突变，或其两种调节蛋白NIPBL和HDAC8的基因突变。HDAC8是人类SMC3赖氨酸脱乙酰酶，是细胞周期中凝集素循环所必需的。到目前为止，最近在被诊断为CDLS的儿童中发现了16种不同的HDAC8错义突变。为了了解这些突变在导致CDLS和重叠表型方面的分子效应，我们充分表征了五个HDAC8突变体的结构和功能：C153F、A188T、I243N、T311M和H334R。X射线晶体结构表明，每个突变都会导致局部结构变化，从而损害催化和/或热稳定性。例如，C153F突变触发构象变化，阻断醋酸盐产物释放通道，导致仅有2%的剩余催化活性。相反，H334R突变会导致远离活性部位的多肽环结构发生变化，并导致91%的剩余活性，但该突变的热稳定性显著受损。值得注意的是，这些突变体的催化活性可以在体外被HDAC8激活剂N-(苯基氨基硫酰基)苯甲酰胺部分或全部挽救。这些结果表明，HDAC8激活剂在寻找治疗CDLS的新治疗策略方面可能是有用的线索。
Cornelia de Lange Syndrome (CdLS) is a multiple congenital anomaly disorder resulting from mutations in genes that encode the core components of the cohesin complex, SMC1A, SMC3, and RAD21, or two of its regulatory proteins, NIPBL and HDAC8. HDAC8 is the human SMC3 lysine deacetylase required for cohesin recycling in the cell cycle. To date, 16 different missense mutations in HDAC8 have recently been identified in children diagnosed with CdLS. To understand the molecular effects of these mutations in causing CdLS and overlapping phenotypes, we have fully characterized the structure and function of five HDAC8 mutants: C153F, A188T, I243N, T311M, and H334R. X-ray crystal structures reveal that each mutation causes local structural changes that compromise catalysis and/or thermostability. For example, the C153F mutation triggers conformational changes that block acetate product release channels, resulting in only 2% residual catalytic activity. In contrast, the H334R mutation causes structural changes in a polypeptide loop distant from the active site and results in 91% residual activity, but the thermostability of this mutant is significantly compromised. Strikingly, the catalytic activity of these mutants can be partially or fully rescued in vitro by the HDAC8 activator N-(phenylcarbamothioyl)benzamide. These results suggest that HDAC8 activators might be useful leads in the search for new therapeutic strategies in managing CdLS.
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影响因子：
15
作者：
Kunze MB;Wright DW;Werbeck ND;Kirkpatrick J;Coveney PV;Hansen DF
通讯作者：
Hansen DF
影响因子：
16
作者：
Beckouët F;Hu B;Roig MB;Sutani T;Komata M;Uluocak P;Katis VL;Shirahige K;Nasmyth K
通讯作者：
Nasmyth K
DOI：
10.1111/j.1749-6632.2008.03450.x
发表时间：
2009-01-01
期刊：
YEAR IN HUMAN AND MEDICAL GENETICS 2009
影响因子：
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作者：
Dorsett, Dale;Krantz, Ian D.
通讯作者：
Krantz, Ian D.
影响因子：
2.7
作者：
Haider, Shozeb;Joseph, Caleb G.;Neidle, Stephen;Fierke, Carol A.;Fuchter, Matthew J.
通讯作者：
Fuchter, Matthew J.
影响因子：
9.8
作者：
Deardorff, Matthew A.;Kaur, Maninder;Krantz, Ian D.
通讯作者：
Krantz, Ian D.