Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
Crystal structure of the N-terminal domain of human CDC73 and its implications for the hyperparathyroidism-jaw tumor (HPT-JT) syndrome.
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人 CDC73 N 端结构域的晶体结构及其对甲状旁腺功能亢进症下颌肿瘤 (HPT-JT) 综合征的影响。
DOI：
10.1038/s41598-017-15715-9
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发表时间：
2017-11-15
影响因子：
4.6
通讯作者：
Xu W
中科院分区：
文献类型：
--
作者：
Sun W;Kuang XL;Liu YP;Tian LF;Yan XX;Xu W
CDC73/副纤维蛋白是Paf1复合体(PAF1C)的重要组成部分，参与转录延长和组蛋白修饰。人类CDC73/HRPT2基因突变与甲状旁腺功能亢进-颌骨肿瘤(HPT-JT)综合征有关，HPT-JT综合征是一种常染色体显性遗传病。CDC73/副纤维蛋白最初被认为是通过抑制细胞周期蛋白D1和c-myc基因抑制细胞增殖而被认为是一种肿瘤抑制因子。近年来，它还通过激活典型的Wnt/β-Catenin信号通路而显示出致癌特征。在这里，通过有限的蛋白质降解分析，我们证明了进化上保守的人CDC73 N端111个残基形成了一个球状折叠结构域(hCDC73-NTD)。我们测定了hCDC73-NTD的晶体结构，其分辨率为1.02 ä，揭示了一个新的蛋白质折叠。CDC73-NTD在其表面含有一条延伸的疏水凹槽，这可能是其功能的重要组成部分。大多数与HPT-JT综合征相关的致病CDC73错义突变位于编码CDC73-NTD的区域。我们的晶体和生化数据表明，大多数CDC73错义突变破坏了hCDC73-NTD疏水核心的折叠，而其他突变，如K34Q突变体，则降低了其热稳定性。总体而言，我们的结果为了解CDC73的结构和功能及其与HPT-JT综合征和其他疾病的关系提供了坚实的结构基础。
CDC73/Parafibromin is a critical component of the Paf1 complex (PAF1C), which is involved in transcriptional elongation and histone modifications. Mutations of the human CDC73/HRPT2 gene are associated with hyperparathyroidism-jaw tumor (HPT-JT) syndrome, an autosomal dominant disorder. CDC73/parafibromin was initially recognized as a tumor suppressor by inhibiting cell proliferation via repression of cyclin D1 and c-myc genes. In recent years, it has also shown oncogenic features by activating the canonical Wnt/β-catenin signal pathway. Here, through limited proteolysis analysis, we demonstrate that the evolutionarily conserved human CDC73 N-terminal 111 residues form a globularly folded domain (hCDC73-NTD). We have determined a crystal structure of hCDC73-NTD at 1.02 Å resolution, which reveals a novel protein fold. CDC73-NTD contains an extended hydrophobic groove on its surface that may be important for its function. Most pathogenic CDC73 missense mutations associated with the HPT-JT syndrome are located in the region encoding CDC73-NTD. Our crystal and biochemical data indicate that most CDC73 missense mutations disrupt the folding of the hydrophobic core of hCDC73-NTD, while others such as the K34Q mutant reduce its thermostability. Overall, our results provide a solid structural basis for understanding the structure and function of CDC73 and its association with the HPT-JT syndrome and other diseases.
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去磷酸化的parafibromin是Wnt/HedgeHog/Notch途径的转录共激活因子。
影响因子：
16.6
作者：
Kikuchi, Ippei;Takahashi-Kanemitsu, Atsushi;Sakiyama, Natsuki;Tang, Chao;Tang, Pei-Jung;Noda, Saori;Nakao, Kazuki;Kassai, Hidetoshi;Sato, Toshiro;Aiba, Atsu;Hatakeyama, Masanori
通讯作者：
Hatakeyama, Masanori
影响因子：
3.7
作者：
Pazienza V;la Torre A;Baorda F;Alfarano M;Chetta M;Muscarella LA;Battista C;Copetti M;Kotzot D;Kapelari K;Al-Abdulrazzaq D;Perlman K;Sochett E;Cole DE;Pellegrini F;Canaff L;Hendy GN;D'Agruma L;Zelante L;Carella M;Scillitani A;Guarnieri V
通讯作者：
Guarnieri V
影响因子：
64.5
作者：
Kim J;Guermah M;Roeder RG
通讯作者：
Roeder RG
对酿酒酵母转录因子 Cdc73 保守 C 端结构域的晶体学分析揭示了 GTP 酶样折叠。
DOI：
10.1107/s0907444912017325
发表时间：
2012-08-01
影响因子：
2.2
作者：
Chen, Hongkai;Shi, Nuo;Niu, Liwen
通讯作者：
Niu, Liwen
影响因子：
3.5
作者：
Hahn, Michael A.;Marsh, Deborah J.
通讯作者：
Marsh, Deborah J.