HIV-1 Tat binds to SH3 domains: cellular and viral outcome of Tat/Grb2 interaction.
HIV-1 Tat binds to SH3 domains: cellular and viral outcome of Tat/Grb2 interaction.
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DOI：
10.1016/j.bbamcr.2011.06.012
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发表时间：
2011-10
期刊：
影响因子：
--
通讯作者：
Peruzzi F
中科院分区：
文献类型：
--
作者：
Rom S;Pacifici M;Passiatore G;Aprea S;Waligorska A;Del Valle L;Peruzzi F
Src-同源性3（SH 3）结构域是最常见的蛋白质识别模块（PRM）之一，在信号转导途径和多种病理学如癌症和AIDS中被代表。Grb 2（生长因子受体结合蛋白2）是一种含有两个SH 3结构域的衔接蛋白，参与受体酪氨酸激酶（RTK）信号转导途径。HIV-1反式激活因子达特是病毒复制所必需的，并且已显示其直接或间接地结合到几种宿主蛋白质，解除其功能。在这项研究中，我们展示了细胞因子Grb 2和HIV-1反式激活蛋白达特之间的相互作用。这种结合由达特的富含脯氨酸的序列和Grb 2的SH 3结构域介导。由于衔接蛋白Grb 2参与多种信号通路，我们表征了达特/Grb 2相互作用对众所周知的IGF-1 R/Raf/MAPK级联的至少一种可能的下游效应。我们发现，达特与Grb 2的结合损害Raf/MAPK通路的激活，同时增强PKA/Raf抑制通路。达特/Grb 2相互作用还通过抑制Tat介导的HIV-1 LTR的反式激活和感染的原代小胶质细胞中的病毒复制来影响病毒功能。
The Src-homology 3 (SH3) domain is one of the most frequent protein recognition modules (PRMs), being represented in signal transduction pathways and in several pathologies such as cancer and AIDS. Grb2 (growth factor receptor-bound protein 2) is an adaptor protein that contains two SH3 domains and is involved in receptor tyrosine kinase (RTK) signal transduction pathways. The HIV-1 transactivator factor Tat is required for viral replication and it has been shown to bind directly or indirectly to several host proteins, deregulating their functions. In this study, we show interaction between the cellular factor Grb2 and the HIV-1 trans-activating protein Tat. The binding is mediated by the proline-rich sequence of Tat and the SH3 domain of Grb2. As the adaptor protein Grb2 participates in a wide variety of signaling pathways, we characterized at least one of the possible downstream effects of the Tat/Grb2 interaction on the well-known IGF-1R/Raf/MAPK cascade. We show that the binding of Tat to Grb2 impairs activation of the Raf/MAPK pathway, while potentiating the PKA/Raf inhibitory pathway. The Tat/Grb2 interaction affects also viral function by inhibiting the Tat-mediated transactivation of HIV-1 LTR and viral replication in infected primary microglia.
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