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Molecular basis for modulation of biological function by alternate splicing of the Wilms' tumor suppressor protein.通过肾母细胞瘤抑癌蛋白的可变剪接调节生物学功能的分子基础。
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11932-5. doi: 10.1073/pnas.97.22.11932.
2
Alternative splicing of Wilms' tumor suppressor protein modulates DNA binding activity through isoform-specific DNA-induced conformational changes.肾母细胞瘤抑癌蛋白的可变剪接通过异构体特异性的DNA诱导构象变化调节DNA结合活性。
Biochemistry. 2000 May 9;39(18):5341-8. doi: 10.1021/bi9926678.
3
Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways.威尔姆斯肿瘤抑制基因wt1的可变剪接转录本产物具有改变的DNA结合特异性,并以不同方式调节转录。
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4
Differential function of Wilms' tumor gene WT1 splice isoforms in transcriptional regulation.肾母细胞瘤基因WT1剪接异构体在转录调控中的差异功能。
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A novel target for the Wilms' tumour suppressor protein (WT1) is bound by a unique combination of zinc fingers.威尔姆斯肿瘤抑制蛋白(WT1)的一个新靶点由锌指的独特组合所结合。
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Expression in Xenopus oocytes shows that WT1 binds transcripts in vivo, with a central role for zinc finger one.非洲爪蟾卵母细胞中的表达表明,WT1在体内与转录本结合,锌指1起核心作用。
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RNA Binding by the KTS Splice Variants of Wilms' Tumor Suppressor Protein WT1.WT1 肿瘤抑制蛋白 KTS 剪接变异体的 RNA 结合。
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The Wilms' tumor gene WT1 can regulate genes involved in sex determination and differentiation: SRY, Müllerian-inhibiting substance, and the androgen receptor.肾母细胞瘤基因WT1可调控参与性别决定和分化的基因:SRY、苗勒管抑制物质和雄激素受体。
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The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts.可变剪接在蛋白质组中的作用:重新连接蛋白质相互作用组,将旧功能置于新环境中。
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Single-Cell RNA Sequencing Reveals mRNA Splice Isoform Switching during Kidney Development.单细胞 RNA 测序揭示了肾脏发育过程中 mRNA 剪接异构体的转换。
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Testis formation in XX individuals resulting from novel pathogenic variants in Wilms' tumor 1 () gene.由威尔姆斯瘤1(WT1)基因的新型致病变异导致的XX个体睾丸形成。
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10
Role for first zinc finger of WT1 in DNA sequence specificity: Denys-Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites.WT1 第一个锌指在 DNA 序列特异性中的作用:与 Denys-Drash 综合征相关的 WT1 突变体在 ZF1 中增强了对一组 WT1 结合位点的亲和力。
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本文引用的文献

1
Alternative splicing of Wilms' tumor suppressor protein modulates DNA binding activity through isoform-specific DNA-induced conformational changes.肾母细胞瘤抑癌蛋白的可变剪接通过异构体特异性的DNA诱导构象变化调节DNA结合活性。
Biochemistry. 2000 May 9;39(18):5341-8. doi: 10.1021/bi9926678.
2
DNA-induced alpha-helix capping in conserved linker sequences is a determinant of binding affinity in Cys(2)-His(2) zinc fingers.保守连接序列中DNA诱导的α-螺旋封端是Cys(2)-His(2)锌指结合亲和力的决定因素。
J Mol Biol. 2000 Jan 28;295(4):719-27. doi: 10.1006/jmbi.1999.3406.
3
Temperature dependence of intramolecular dynamics of the basic leucine zipper of GCN4: implications for the entropy of association with DNA.GCN4碱性亮氨酸拉链分子内动力学的温度依赖性:对与DNA结合熵的影响
J Mol Biol. 1999 Feb 5;285(5):2133-46. doi: 10.1006/jmbi.1998.2429.
4
WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes.WT1以一种异构体依赖的方式与剪接因子U2AF65相互作用,并可被整合到剪接体中。
Genes Dev. 1998 Oct 15;12(20):3217-25. doi: 10.1101/gad.12.20.3217.
5
Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.弗雷泽综合征是由WT1基因的异常可变剪接引起的,导致WT1 +/-KTS剪接异构体的比例发生改变。
Hum Mol Genet. 1998 Apr;7(4):709-14. doi: 10.1093/hmg/7.4.709.
6
Comparison of the DNA binding characteristics of the related zinc finger proteins WT1 and EGR1.相关锌指蛋白WT1和EGR1的DNA结合特性比较。
Biochemistry. 1998 Feb 17;37(7):2051-8. doi: 10.1021/bi9717993.
7
Donor splice-site mutations in WT1 are responsible for Frasier syndrome.WT1基因的供体剪接位点突变是弗雷泽综合征的病因。
Nat Genet. 1997 Dec;17(4):467-70. doi: 10.1038/ng1297-467.
8
Solution structure of the first three zinc fingers of TFIIIA bound to the cognate DNA sequence: determinants of affinity and sequence specificity.与同源DNA序列结合的TFIIIA前三个锌指的溶液结构:亲和力和序列特异性的决定因素
J Mol Biol. 1997 Oct 17;273(1):183-206. doi: 10.1006/jmbi.1997.1291.
9
Domain packing and dynamics in the DNA complex of the N-terminal zinc fingers of TFIIIA.TFIIIA N 端锌指结构域在 DNA 复合物中的结构组装与动力学
Nat Struct Biol. 1997 Aug;4(8):605-8. doi: 10.1038/nsb0897-605.
10
Cocrystal structure of YY1 bound to the adeno-associated virus P5 initiator.与腺相关病毒P5起始子结合的YY1共晶体结构。
Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13577-82. doi: 10.1073/pnas.93.24.13577.

通过肾母细胞瘤抑癌蛋白的可变剪接调节生物学功能的分子基础。

Molecular basis for modulation of biological function by alternate splicing of the Wilms' tumor suppressor protein.

作者信息

Laity J H, Dyson H J, Wright P E

机构信息

Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

出版信息

Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11932-5. doi: 10.1073/pnas.97.22.11932.

DOI:10.1073/pnas.97.22.11932
PMID:11050227
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC17272/
Abstract

Alternate splicing, leading to the insertion of the tripeptide KTS in the linker between the third and fourth C(2)H(2) zinc fingers, changes both the DNA-binding function and the subnuclear localization of the Wilms' tumor suppressor protein (WT1). We have used NMR relaxation experiments to determine the molecular basis for the differing DNA recognition properties of the WT1-KTS and WT1+KTS isoforms. Our results show that the KTS insertion increases the flexibility of the linker between fingers 3 and 4 and abrogates binding of the fourth zinc finger to its cognate site in the DNA major groove. This represents a mechanism whereby a single zinc-finger gene can be used, through alternate splicing, to fulfill different functions in the cell.

摘要

可变剪接导致在第三个和第四个C(2)H(2)锌指之间的连接区插入三肽KTS,这改变了威尔姆斯肿瘤抑制蛋白(WT1)的DNA结合功能和亚核定位。我们利用核磁共振弛豫实验来确定WT1-KTS和WT1+KTS异构体不同DNA识别特性的分子基础。我们的结果表明,KTS插入增加了3号和4号锌指之间连接区的灵活性,并消除了第四个锌指与DNA大沟中其同源位点的结合。这代表了一种机制,通过可变剪接,单个锌指基因可用于在细胞中发挥不同功能。