Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases
文献类型：期刊论文
| 作者 | Zhang, Lun2,3; Wang, Jian-Chuan4; Hou, Li2,3 ; Cao, Peng-Rong2,3; Wu, Li5; Zhang, Qian-Sen1,6; Yang, Huai-Yu1,6; Zang, Yi2,3; Ding, Jian-Ping4; Li, Jia2,3,5
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| 刊名 | SCIENTIFIC REPORTS
 |
| 出版日期 | 2015-05-11 |
| 卷号 | 5 |
| ISSN号 | 2045-2322 |
| DOI | 10.1038/srep10115 |
| 文献子类 | Article |
| 英文摘要 | The His-x-Asp (HxD) motif is one of the most conserved structural components of the catalytic core of protein kinases; however, the functional role of the conserved histidine is unclear. Here we report that replacement of the HxD-histidine with Arginine or Phenylalanine in Aurora A abolishes both the catalytic activity and auto-phosphorylation, whereas the Histidine-to-tyrosine impairs the catalytic activity without affecting its auto-phosphorylation. Comparisons of the crystal structures of wild-type (WT) and mutant Aurora A demonstrate that the impairment of the kinase activity is accounted for by (1) disruption of the regulatory spine in the His-to-Arg mutant, and (2) change in the geometry of backbones of the Asp-Phe-Gly (DFG) motif and the DFG-1 residue in the His-to-Tyr mutant. In addition, bioinformatics analyses show that the HxD-histidine is a mutational hotspot in tumor tissues. Moreover, the H174R mutation of the HxD-histidine, in the tumor suppressor LKB1 abrogates the inhibition of anchorage-independent growth of A549 cells by WT LKB1. Based on these data, we propose that the HxD-histidine is involved in a conserved inflexible organization of the catalytic core that is required for the kinase activity. Mutation of the HxD-histidine may also be involved in the pathogenesis of some diseases including cancer. |
| WOS关键词 | LUNG-CANCER ; ACTIVATION ; PHOSPHORYLATION ; MECHANISMS ; MUTATIONS ; INACTIVATION ; CONFORMATION ; DOMAIN |
| 资助项目 | National Science Foundation of China[81125023] ; National Natural Science Foundation of China[81173033] ; Chinese Academy of Science[XDA01040303] ; Program of Shanghai Subject Chief Scientist[13XD1404300] |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:000354274000001 |
| 出版者 | NATURE PUBLISHING GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276531]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Zang, Yi |
| 作者单位 | 1.Chinese Acad Sci, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, State Key Lab Mol Biol, Shanghai 200031, Peoples R China; 5.E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China; 6.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Lun,Wang, Jian-Chuan,Hou, Li,et al. Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases[J]. SCIENTIFIC REPORTS,2015,5. |
| APA | Zhang, Lun.,Wang, Jian-Chuan.,Hou, Li.,Cao, Peng-Rong.,Wu, Li.,...&Li, Jia.(2015).Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases.SCIENTIFIC REPORTS,5. |
| MLA | Zhang, Lun,et al."Functional Role of Histidine in the Conserved His-x-Asp Motif in the Catalytic Core of Protein Kinases".SCIENTIFIC REPORTS 5(2015). |
入库方式： OAI收割
来源：上海药物研究所
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