Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain
文献类型：期刊论文
| 作者 | Zhu, Jiang2; Li, Shuangli2,3; Ramelot, Theresa A.1,4; Kennedy, Michael A.1,4; Liu, Maili2; Yang, Yunhuang2 |
| 刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
 |
| 出版日期 | 2018-02-05 |
| 卷号 | 496期号:2页码:575-581 |
| 关键词 | Transforming Growth-interacting Factor 1 Holoprosencephaly Nmr Structure Dna Binding |
| ISSN号 | 0006-291X |
| DOI | 10.1016/j.bbrc.2018.01.099 |
| 文献子类 | Article |
| 英文摘要 | Human protein TGIF1 is an essential regulator of cell fate with broad roles in different tissues, and has been implicated in holoprosencephaly (HPE) and many cancers. The function of TGIFI in transcriptional regulation depends on its three-amino acid loop extension (TALE) type of homeodomain (HD). Two missense mutations that led to P192A and R219C substitutions in TGIFI-HD were previously found in HPE patients and suggested to be the causes for these cases. However, how these mutations affected TGIF1 function has not been investigated from a structural view. Here, we investigated the roles of P192 and R219 in TGIFI-HD structure packing through determining the NMR structure of TGIF1-HD. Surprisingly, P192 and R219 were found to play roles in packing alpha 1 and alpha 2 to alpha 3 together with A190 and F215 through side-chain interactions. Circular dichroism (CD) showed that P192A and R219C mutants displayed structural change and less folding compared with wild-type TGIFI-HD, and H-1-N-15 HSQC spectrum of P192A mutant exhibited chemical shift perturbations in all three helices of TGIFI-HD. Thus, it is suggested that P192A and R219C mutations led to structure disturbances of TGIF1-HD, which subsequently reduced the DNA-binding affinity of TGIF1-HD by 23-fold and 10-fold respectively, as revealed by the isothermal titration calorimetry (ITC) experiments. Our study provides structural insights of the probable pathogenesis mechanism of two TGIF1-related HPE cases, and evidences for the roles of P192 and R219 in HD folding. (C) 2018 Elsevier Inc. All rights reserved. |
| WOS关键词 | TG-INTERACTING-FACTOR ; PROTEIN STRUCTURES ; CARCINOMA ; GENE |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000424313500050 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 资助机构 | National Key R&D Program of China(2016YFA051201) ; National Key R&D Program of China(2016YFA051201) ; National Natural Sciences Foundation of China(21575155) ; National Natural Sciences Foundation of China(21575155) ; Hundred Talent Program by Chinese Academy of Sciences ; Hundred Talent Program by Chinese Academy of Sciences ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Key R&D Program of China(2016YFA051201) ; National Key R&D Program of China(2016YFA051201) ; National Natural Sciences Foundation of China(21575155) ; National Natural Sciences Foundation of China(21575155) ; Hundred Talent Program by Chinese Academy of Sciences ; Hundred Talent Program by Chinese Academy of Sciences ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Key R&D Program of China(2016YFA051201) ; National Key R&D Program of China(2016YFA051201) ; National Natural Sciences Foundation of China(21575155) ; National Natural Sciences Foundation of China(21575155) ; Hundred Talent Program by Chinese Academy of Sciences ; Hundred Talent Program by Chinese Academy of Sciences ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Key R&D Program of China(2016YFA051201) ; National Key R&D Program of China(2016YFA051201) ; National Natural Sciences Foundation of China(21575155) ; National Natural Sciences Foundation of China(21575155) ; Hundred Talent Program by Chinese Academy of Sciences ; Hundred Talent Program by Chinese Academy of Sciences ; National Institute of General Medical Sciences of USA(U54-GM094597) ; National Institute of General Medical Sciences of USA(U54-GM094597) |
| 源URL | [http://ir.wipm.ac.cn/handle/112942/12866]  |
| 专题 | 中国科学院武汉物理与数学研究所 |
| 通讯作者 | Liu, Maili; Yang, Yunhuang |
| 作者单位 | 1.Miami Univ, Dept Chem & Biochem, Oxford, OH 45056 USA 2.Chinese Acad Sci, Wuhan Inst Phys & Math, Wuhan Ctr Magnet Resonance, State Key Lab Magnet Resonance & Atom Mol Phys, Wuhan 430071, Hubei, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Miami Univ, Northeast Struct Genom Consortium, Oxford, OH 45056 USA |
| 推荐引用方式 GB/T 7714 | Zhu, Jiang,Li, Shuangli,Ramelot, Theresa A.,et al. Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2018,496(2):575-581. |
| APA | Zhu, Jiang,Li, Shuangli,Ramelot, Theresa A.,Kennedy, Michael A.,Liu, Maili,&Yang, Yunhuang.(2018).Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,496(2),575-581. |
| MLA | Zhu, Jiang,et al."Structural insights into the impact of two holoprosencephaly-related mutations on human TGIF1 homeodomain".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 496.2(2018):575-581. |
入库方式： OAI收割
来源：武汉物理与数学研究所
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