Molecular Dynamics of the Recruitment of Immunoreceptor Signaling Module DAP12 Homodimer to Lipid Raft Boundary Regulated by PIP2
Molecular Dynamics of the Recruitment of Immunoreceptor Signaling Module DAP12 Homodimer to Lipid Raft Boundary Regulated by PIP2
复制标题
PIP2 调控的免疫受体信号模块 DAP12 同二聚体募集至脂筏边界的分子动力学
DOI：
10.1021/acs.jpcb.9b11095
复制
发表时间：
2020-01-23
影响因子：
3.3
通讯作者：
Wei, Peng
中科院分区：
文献类型：
--
作者：
Dong, Ruijuan;Tan, Yan;Wei, Peng
质膜的脂筏微区参与各种生物学和病理学过程。脂筏参与T细胞受体（TCR）信号转导已被广泛研究，而这些结构在自然杀伤（NK）细胞中通过DAP 12的免疫受体信号传导中的作用在很大程度上仍然未知。在这里，我们证明了4，5-二磷酸磷脂酰肌醇（PIP 2）脂质定位于我们的粗粒（CG）模型筏形成膜中的脂筏边界，并且这种带负电荷的脂质通过富含碱性的区域之间的蛋白质-脂质相互作用将DAP 12同二聚体招募到脂筏边界和信号传导免疫受体基于酪氨酸的激活基序（ITAM）的DAP 12和PIP 2。此外，我们的研究结果表明，蛋白质-脂质相互作用可以被Ca 2+破坏，Ca 2+竞争性结合PIP 2而不是DAP 12。结果，DAP 12同源二聚体的胞质区域从膜解离回到非筏结构域，并且ITAM被暴露以允许进一步的下游信号传导。这些发现为理解NK细胞受膜微环境调控的信号转导机制提供了基础。
Lipid raft microdomain of the plasma membrane is implicated in various biological and pathological processes. The involvement of lipid raft in T cell receptor (TCR) signal transduction has been widely studied, whereas the role of these structures in immunoreceptor signaling by DAP12 in natural killing (NK) cells remains largely unknown. Here, we demonstrate that phosphatidylinositol 4,5-bisphosphate (PIP2) lipid localized to lipid raft boundary in our coarse-grained (CG) model raft-forming membrane, and this negatively charged lipid recruits DAP12 homodimer into lipid raft boundary through protein-lipid interaction between the basic-rich regions and signaling immunoreceptor tyrosine-based activation motifs (ITAMs) of DAP12 and PIP2. Furthermore, our results reveal that the protein-lipid interaction can be disrupted by Ca2+, which competitively binds to PIP2 instead of DAP12. As a result, the cytoplasmic region of DAP12 homodimer is dissociated from the membrane back to the nonraft domain, and the ITAMs are exposed to allow further downstream signaling. These findings provide fundamental insights to understand the mechanism of signal transduction in NK cells regulated by membrane microenvironment.