Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization
Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization
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DOI：
10.1128/mcb.23.1.186-194.2003
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发表时间：
2003-01-01
影响因子：
5.3
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Hsieh, JJD;Ernst, P;Korsmeyer, SJ
混合谱系白血病基因（MLL、ALL 1、HRX）编码一种与三胸果蝇同源的3，969个氨基酸的核蛋白，并且是维持Hox基因正确表达所必需的。人类白血病中的染色体易位破坏了MLL（11 q23），在MLL的N末端和多个易位伴侣之间产生嵌合蛋白。在这里，我们报告说，MLL通常在两个保守的网站（D/GADD和D/GVDD）切割和这些网站的突变废除蛋白水解。MLL切割产生N-末端p320（N320）和C-末端p180（C180）片段，其形成定位于亚核区室的稳定复合物。N320的FYRN结构域直接与C180的FYRC和SET结构域相互作用。破坏N320和C180之间的相互作用导致N320水平的显著降低和C180重新分布到弥散核模式。这些数据表明一个模型，其中动态裂解后协会赋予稳定性N320和正确的核亚定位的复合物，以控制N320的靶基因的可用性。这预示了将失去与C180复合的能力的白血病MLL融合蛋白具有由融合配偶体赋予的稳定性，从而提供了改变靶基因表达的一种机制。
The mixed-lineage leukemia gene (MLL, ALL1, HRX) encodes a 3,969-amino-acid nuclear protein homologous to Drosophila trithorax and is required to maintain proper Hox gene expression. Chromosome translocations in human leukemia disrupt MLL (11q23), generating chimeric proteins between the N terminus of MLL and multiple translocation partners. Here we report that MLL is normally cleaved at two conserved sites (D/GADD and D/GVDD) and that mutation of these sites abolishes the proteolysis. MLL cleavage generates N-terminal p320 (N320) and C-terminal p180 (C180) fragments, which form a stable complex that localizes to a subnuclear compartment. The FYRN domain of N320 directly interacts with the FYRC and SET domains of C180. Disrupting the interaction between N320 and C180 leads to a marked decrease in the level of N320 and a redistribution of C180 to a diffuse nuclear pattern. These data suggest a model in which a dynamic post-cleavage association confers stability to N320 and correct nuclear sublocalization of the complex, to control the availability of N320 for target genes. This predicts that MLL fusion proteins of leukemia which would lose the ability to complex with C180 have their stability conferred instead by the fusion partners, thus providing one mechanism for altered target gene expression.