Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex
Direct interaction between the PRDM3 and PRDM16 tumor suppressors and the NuRD chromatin remodeling complex
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DOI：
10.1093/nar/gky1192
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发表时间：
2019-02-20
影响因子：
14.9
通讯作者：
Arrowsmith, Cheryl H.
中科院分区：
文献类型：
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作者：
Ivanochko, Danton;Halabelian, Levon;Arrowsmith, Cheryl H.
染色质相关蛋白的异常亚型表达可以诱导与疾病相关的表观遗传程序。 MDS1 和 EVI1 复合基因座 (MECOM) 编码 PRDM3（一种具有 N 端 PR-SET 结构域的蛋白质）以及较短的亚型 EVI1（缺乏包含 PR-SET 结构域 (PR) 的 N 端）。在多种恶性肿瘤中观察到 MECOM 亚型的不平衡表达，表明 EVI1 是一种癌基因，而 PRDM3 则被认为通过未知机制发挥肿瘤抑制基因的作用。为了阐明这些 N 端残基的功能特征，我们比较了 PRDM3 及其密切相关的旁系同源物 PRDM16 的全长和 PR 亚型的蛋白质相互作用组。与 PR 同工型不同，两种全长同工型都表现出与 NuRD 染色质重塑复合物成分（尤其是 RBBP4）显着丰富的关联。通常，RBBP4 通过与组蛋白 H3 尾部结合来促进 NuRD 复合物的染色质缔合。我们发现 RBBP4 与 PRDM3 和 PRDM16 的 N 端氨基酸残基结合，通过等温滴定量热法测量，解离常数为 3.0 M。此外，与 RBBP4 复合的 PRDM3 和 PRDM16 N 端肽的高分辨率 X 射线晶体结构揭示了在保守的组蛋白 H3 结合沟内与 RBBP4 的结合。这些数据支持 PRDM3 和 PRDM16 与 NuRD 染色质重塑复合物的亚型特异性相互作用机制。
Aberrant isoform expression of chromatin-associated proteins can induce epigenetic programs related to disease. The MDS1 and EVI1 complex locus (MECOM) encodes PRDM3, a protein with an N-terminal PR-SET domain, as well as a shorter isoform, EVI1, lacking the N-terminus containing the PR-SET domain (PR). Imbalanced expression of MECOM isoforms is observed in multiple malignancies, implicating EVI1 as an oncogene, while PRDM3 has been suggested to function as a tumor suppressor through an unknown mechanism. To elucidate functional characteristics of these N-terminal residues, we compared the protein interactomes of the full-length and PR isoforms of PRDM3 and its closely related paralog, PRDM16. Unlike the PR isoforms, both full-length isoforms exhibited a significantly enriched association with components of the NuRD chromatin remodeling complex, especially RBBP4. Typically, RBBP4 facilitates chromatin association of the NuRD complex by binding to histone H3 tails. We show that RBBP4 binds to the N-terminal amino acid residues of PRDM3 and PRDM16, with a dissociation constant of 3.0 M, as measured by isothermal titration calorimetry. Furthermore, high-resolution X-ray crystal structures of PRDM3 and PRDM16 N-terminal peptides in complex with RBBP4 revealed binding to RBBP4 within the conserved histone H3-binding groove. These data support a mechanism of isoform-specific interaction of PRDM3 and PRDM16 with the NuRD chromatin remodeling complex.