Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding.
Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding.
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DOI：
10.1016/j.str.2012.11.011
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发表时间：
2013-01-08
期刊：
影响因子：
5.7
通讯作者：
Bushweller, John H.
中科院分区：
文献类型：
--
作者：
Leach, Benjamin I.;Kuntimaddi, Aravinda;Schmidt, Charles R.;Cierpicki, Tomasz;Johnson, Stephanie A.;Bushweller, John H.
混合谱系白血病（MLL）融合蛋白通过延伸因子向HOX启动子的组成性募集引起造血细胞的致癌转化，导致靶基因的过表达。MLL融合伴侣反式激活的结构基础仍然不确定。我们发现，ANC1同源结构域（AHD）的AF9，最常见的MLL易位的合作伙伴之一，本质上是无序的，并通过耦合折叠和绑定招募多个转录因子。我们确定的结构的AF9 AHD的复合物与延伸因子AF4，并表明，脂肪族残基，这是保守的AF9结合伙伴的每一个形成一个组成部分的疏水核心的复杂。NMR弛豫测量表明AF9保留了显著的动力学行为，这可能有助于无序伴侣之间的交换。我们认为，AF9作为一个信号枢纽，通过动态募集正常造血和急性白血病中的辅因子来调节转录。
Mixed Lineage Leukemia (MLL) fusion proteins cause oncogenic transformation of hematopoietic cells by constitutive recruitment of elongation factors to HOX promoters, resulting in over-expression of target genes. The structural basis of transactivation by MLL fusion partners remains undetermined. We show that the ANC1 Homology Domain (AHD) of AF9, one of the most common MLL translocation partners, is intrinsically disordered and recruits multiple transcription factors through coupled folding and binding. We determined the structure of the AF9 AHD in complex with the elongation factor AF4, and show that aliphatic residues which are conserved in each of the AF9 binding partners form an integral part of the hydrophobic core of the complex. NMR relaxation measurements show AF9 retains significant dynamic behavior which may facilitate exchange between disordered partners. We propose that AF9 functions as a signaling hub which regulates transcription through dynamic recruitment of co-factors in normal hematopoiesis and in acute leukemia.
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影响因子：
64.8
作者：
Demarest, SJ;Martinez-Yamout, M;Wright, PE
通讯作者：
Wright, PE
影响因子：
50.3
作者：
Muntean AG;Tan J;Sitwala K;Huang Y;Bronstein J;Connelly JA;Basrur V;Elenitoba-Johnson KS;Hess JL
通讯作者：
Hess JL
DOI：
10.1016/j.cub.2009.02.055
发表时间：
2009-04-28
期刊：
Current biology : CB
影响因子：
--
作者：
Chopra VS;Hong JW;Levine M
通讯作者：
Levine M
影响因子：
4.8
作者：
Bárdos, JI;Saurin, AJ;Freemont, PS
通讯作者：
Freemont, PS
影响因子：
11.4
作者：
Meyer, C.;Kowarz, E.;Marschalek, R.
通讯作者：
Marschalek, R.