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人源 cGAS-DNA 复合物结构揭示了增强免疫监视的控制。

Structure of the Human cGAS-DNA Complex Reveals Enhanced Control of Immune Surveillance.

机构信息

Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

出版信息

Cell. 2018 Jul 12;174(2):300-311.e11. doi: 10.1016/j.cell.2018.06.026.

DOI:10.1016/j.cell.2018.06.026
PMID:30007416
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6084792/
Abstract

Cyclic GMP-AMP synthase (cGAS) recognition of cytosolic DNA is critical for immune responses to pathogen replication, cellular stress, and cancer. Existing structures of the mouse cGAS-DNA complex provide a model for enzyme activation but do not explain why human cGAS exhibits severely reduced levels of cyclic GMP-AMP (cGAMP) synthesis compared to other mammals. Here, we discover that enhanced DNA-length specificity restrains human cGAS activation. Using reconstitution of cGAMP signaling in bacteria, we mapped the determinant of human cGAS regulation to two amino acid substitutions in the DNA-binding surface. Human-specific substitutions are necessary and sufficient to direct preferential detection of long DNA. Crystal structures reveal why removal of human substitutions relaxes DNA-length specificity and explain how human-specific DNA interactions favor cGAS oligomerization. These results define how DNA-sensing in humans adapted for enhanced specificity and provide a model of the active human cGAS-DNA complex to enable structure-guided design of cGAS therapeutics.

摘要

环鸟苷酸-腺苷酸合酶 (cGAS) 识别细胞溶质 DNA 对于免疫反应病原体复制、细胞应激和癌症至关重要。现有的小鼠 cGAS-DNA 复合物结构为酶激活提供了模型，但不能解释为什么与其他哺乳动物相比，人 cGAS 表现出严重降低的环鸟苷酸-腺苷酸 (cGAMP) 合成水平。在这里，我们发现增强的 DNA 长度特异性限制了人 cGAS 的激活。我们使用细菌中 cGAMP 信号的重建，将人 cGAS 调节的决定因素映射到 DNA 结合表面的两个氨基酸取代上。人类特异性取代是必需和充分的，以指导对长 DNA 的优先检测。晶体结构揭示了为什么去除人类取代物可以放宽 DNA 长度特异性，并解释了为什么人类特异性 DNA 相互作用有利于 cGAS 寡聚化。这些结果定义了人类中 DNA 感应如何适应增强的特异性，并提供了活性人 cGAS-DNA 复合物的模型，以实现基于结构的 cGAS 治疗药物的设计。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/04c316a549f7/nihms975849f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/ed35351de7e1/nihms975849f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/112a320076d9/nihms975849f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/0041b8079633/nihms975849f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/f7905d4f462e/nihms975849f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/d859302d2674/nihms975849f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/04c316a549f7/nihms975849f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/ed35351de7e1/nihms975849f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/723f31b856a3/nihms975849f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/112a320076d9/nihms975849f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/0041b8079633/nihms975849f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/f7905d4f462e/nihms975849f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/d859302d2674/nihms975849f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fa6/6084792/04c316a549f7/nihms975849f7.jpg

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