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DOI | 10.1038/s41467-018-08032-w |
Evolution of AF6-RAS association and its implications in mixed-lineage leukemia | |
Smith, Matthew J.1,2; Ottoni, Elizabeth1; Ishiyama, Noboru3; Goudreault, Marilyn1; Haman, Andre1; Meyer, Claus4; Tucholska, Monika5; Gasmi-Seabrook, Genevieve3; Menezes, Serena3; Laister, Rob C.3; Minden, Mark D.3,6; Marschalek, Rolf4; Gingras, Anne-Claude7; Trang Hoang1,8; Ikura, Mitsuhiko3,6 | |
2019-01-10 | |
发表期刊 | NATURE COMMUNICATIONS |
ISSN | 2041-1723 |
出版年 | 2017 |
卷号 | 8 |
文章类型 | Article |
语种 | 英语 |
国家 | Canada; Germany |
英文摘要 | Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved alpha-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding of MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000413404800010 |
WOS关键词 | MLL FUSION PROTEINS ; CRYSTAL-STRUCTURE ; ADHERENS JUNCTIONS ; RAS BINDING ; EFFECTOR ; TRANSFORMATION ; DIMERIZATION ; ACTIVATION ; AFADIN ; DOMAIN |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204155 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3T 1J4, Canada; 2.Univ Montreal, Dept Pathol & Cell Biol, Fac Med, Montreal, PQ H3T 1J4, Canada; 3.Princess Margaret Canc Ctr, Campbell Family Canc Res Inst, Toronto, ON M5G 2C1, Canada; 4.Goethe Univ Frankfurt, Inst Pharmaceut Biol, D-60323 Frankfurt, Germany; 5.Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada; 6.Univ Toronto, Dept Med Biophys, Toronto, ON M5G 1L7, Canada; 7.Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada; 8.Univ Montreal, Fac Med, Dept Pharmacol, Montreal, PQ H3T 1J4, Canada |
推荐引用方式 GB/T 7714 | Smith, Matthew J.,Ottoni, Elizabeth,Ishiyama, Noboru,et al. Evolution of AF6-RAS association and its implications in mixed-lineage leukemia[J]. NATURE COMMUNICATIONS,2019,8. |
APA | Smith, Matthew J..,Ottoni, Elizabeth.,Ishiyama, Noboru.,Goudreault, Marilyn.,Haman, Andre.,...&Ikura, Mitsuhiko.(2019).Evolution of AF6-RAS association and its implications in mixed-lineage leukemia.NATURE COMMUNICATIONS,8. |
MLA | Smith, Matthew J.,et al."Evolution of AF6-RAS association and its implications in mixed-lineage leukemia".NATURE COMMUNICATIONS 8(2019). |
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