Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Nature. 2012 Feb 12;482(7386):542-6. doi: 10.1038/nature10806.
Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.
Menin 是一种肿瘤抑制蛋白，其缺失或失活会导致多发性内分泌肿瘤 1 型（MEN1），这是一种遗传性常染色体显性肿瘤综合征，其特征是多个内分泌器官发生肿瘤。Menin 与许多蛋白质相互作用，并参与多种细胞过程。Menin 与 JUN 家族转录因子 JUND 结合并抑制其转录活性。几种 MEN1 错义突变破坏了 menin-JUND 相互作用，提示 menin 的肿瘤抑制功能与其抑制 JUND 激活转录之间存在相关性。Menin 还与混合谱系白血病蛋白 1（MLL1）相互作用，后者是一种组蛋白 H3 赖氨酸 4 甲基转移酶，并作为致癌共因子上调基因转录并促进 MLL1-融合蛋白诱导的白血病发生。最近一项关于 menin 将 MLL1 固定在染色质结合因子晶状体上皮衍生生长因子（LEDGF）上的报告表明，menin 是一种分子衔接子，协调多种蛋白质的功能。尽管它很重要，但 menin 如何与许多不同的伴侣相互作用并调节它们的功能仍然知之甚少。在这里，我们展示了人 menin 游离形式及其与 MLL1 或 JUND 或与 MLL1-LEDGF 异二聚体复合物的晶体结构。这些结构表明，menin 包含一个深口袋，以相同的方式结合 MLL1 或 JUND 的短肽，但对转录有相反的影响。menin-JUND 相互作用阻止 JUN N 端激酶（JNK）介导的 JUND 磷酸化并抑制 JUND 诱导的转录。相比之下，menin 通过肽口袋结合转录激活因子 MLL1 促进基因转录，同时仍与染色质锚定蛋白 LEDGF 在由 menin 和 MLL1 共同形成的独特表面上相互作用。
