Single-stranded nucleic acids promote SAMHD1 complex formation
Single-stranded nucleic acids promote SAMHD1 complex formation
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DOI：
10.1007/s00109-013-0995-3
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发表时间：
2013-06-01
影响因子：
4.7
通讯作者：
Lee-Kirsch, Min Ae
中科院分区：
文献类型：
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作者：
Tuengler, Victoria;Staroske, Wolfgang;Lee-Kirsch, Min Ae
包含 SAM 结构域和 HD 结构域的蛋白 1 (SAMHD1) 是一种 dGTP 依赖性三磷酸水解酶，可降解脱氧核糖核苷三磷酸 (dNTP)，从而限制细胞内 dNTP 池。 SAMHD1 突变会导致 Aicardi-GoutiSres 综合征 (AGS)，这是一种类似于先天性病毒感染的炎性脑病，其表型与自身免疫性疾病系统性红斑狼疮重叠。这两种疾病的特征都是通过自身核酸的免疫识别引发抗病毒细胞因子干扰素-α的激活。在这里，我们提供了 SAMHD1 与内源核酸原位关联的第一个直接证据。使用荧光互相关光谱，我们证明 SAMHD1 与 ssRNA 和 ssDNA 特异性相互作用，并确定核酸结合和 SAMHD1 复合物的形成是相互依赖的。与核酸的相互作用和复合物的形成不需要SAM结构域，但依赖于HD结构域和SAMHD1的C端区域。我们最终证明，与 AGS 相关的突变表现出核酸结合和复合物形成受损，这表明与核酸的相互作用是 SAMHD1 功能的一个组成部分。
SAM domain and HD domain-containing protein 1 (SAMHD1) is a dGTP-dependent triphosphohydrolase that degrades deoxyribonucleoside triphosphates (dNTPs) thereby limiting the intracellular dNTP pool. Mutations in SAMHD1 cause Aicardi-GoutiSres syndrome (AGS), an inflammatory encephalopathy that mimics congenital viral infection and that phenotypically overlaps with the autoimmune disease systemic lupus erythematosus. Both disorders are characterized by activation of the antiviral cytokine interferon-alpha initiated by immune recognition of self nucleic acids. Here we provide first direct evidence that SAMHD1 associates with endogenous nucleic acids in situ. Using fluorescence cross-correlation spectroscopy, we demonstrate that SAMHD1 specifically interacts with ssRNA and ssDNA and establish that nucleic acid-binding and formation of SAMHD1 complexes are mutually dependent. Interaction with nucleic acids and complex formation do not require the SAM domain, but are dependent on the HD domain and the C-terminal region of SAMHD1. We finally demonstrate that mutations associated with AGS exhibit both impaired nucleic acid-binding and complex formation implicating that interaction with nucleic acids is an integral aspect of SAMHD1 function.