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首页> 外文期刊>Biochemistry >CD40-Tumor necrosis factor receptor-associated factor (TRAF) interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization
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CD40-Tumor necrosis factor receptor-associated factor (TRAF) interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization

机译：CD40-肿瘤坏死因子受体相关因子（TRAF）相互作用：通过多个TRAF结合位点和TRAF异源寡聚化调节CD40信号传导。

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摘要

CD40 is a TNF receptor superfamily member that provides activation signals in antigen-presenting cells such as B cells, macrophages, and dendritic cells. Multimerization of CD40 by its ligand initiates signaling by recruiting TNF receptor-associated factors (TRAFs) to the CD40 cytoplasmic domain. Recombinant human TRAF proteins overexpressed in insect cells were biochemically characterized and used to finely map TRAF binding regions in the human CD40 cytoplasmic domain. TRAF1, TRAF2, TRAF3, and TRAF6, but not TRAF4 or TRAF5, bound directly to the CD40 cytoplasmic domain. CD40 interactions with TRAF2 and TRAF3 were stronger than the interactions with TRAF1 and TRAF6. Full-length TRAF3 and TRAF5 formed hetero-oligomers, presumably through their predicted isoleucine zippers. TRAF3-TRAF5 hetero-oligomers interacted with CD40, indicating that TRAF5 can be indirectly recruited to the CD40 cytoplasmic domain. Overlapping peptides synthesized on cellulose membranes were used to map each TRAF interaction region. TRAF1, TRAF2, and TRAF3 interacted with the same region. The recognition site for TRAF6 was a nonoverlapping membrane proximal region. Using peptides with progressive deletions, a minimal TRAF1, TRAF2, and TRAF3 binding region was mapped to the PVQET sequence in the CD40 cytoplasmic domain. The minimal region for TRAF6 binding was the sequence QEPQEINF. These studies demonstrate that the CD40 cytoplasmic domain contains two nonoverlapping TRAF binding regions and suggest that TRAF1, TRAF2, and TRAF3 could bind competitively to one site. Relative affinities and competition of individual and hetero-oligomeric TRAF proteins for CD40 binding sites may contribute to receptor specificity and cell-type selectivity in CD40-dependent signaling. [References: 49]
机译：CD40是TNF受体超家族成员，可在抗原呈递细胞（例如B细胞，巨噬细胞和树突状细胞）中提供激活信号。 CD40通过其配体的多聚化通过将TNF受体相关因子（TRAF）募集到CD40胞质域来启动信号传导。对昆虫细胞中过表达的重组人TRAF蛋白进行了生化鉴定，并用于在人CD40细胞质结构域中精确定​​位TRAF结合区。 TRAF1，TRAF2，TRAF3和TRAF6，而不是TRAF4或TRAF5，直接与CD40胞质域结合。 CD40与TRAF2和TRAF3的相互作用比与TRAF1和TRAF6的相互作用更强。全长TRAF3和TRAF5可能通过其预测的异亮氨酸拉链形成了异源寡聚体。 TRAF3-TRAF5异源寡聚体与CD40相互作用，表明TRAF5可以间接募集到CD40胞质域。在纤维素膜上合成的重叠肽用于绘制每个TRAF相互作用区域的图。 TRAF1，TRAF2和TRAF3与同一区域相互作用。 TRAF6的识别位点是不重叠的膜近端区域。使用具有进行性缺失的肽，最小的TRAF1，TRAF2和TRAF3结合区被定位到CD40细胞质域中的PVQET序列。 TRAF6结合的最小区域是序列QEPQEINF。这些研究表明CD40胞质域包含两个不重叠的TRAF结合区，并暗示TRAF1，TRAF2和TRAF3可以竞争性地结合到一个位点。相对亲和力和单个和异源TRAF蛋白对CD40结合位点的竞争可能有助于CD40依赖性信号传导中的受体特异性和细胞类型选择性。 [参考：49]

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