Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization
Crystal Structures of the Full-Length Murine and Human Gasdermin D Reveal Mechanisms of Autoinhibition, Lipid Binding, and Oligomerization
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DOI：
10.1016/j.immuni.2019.04.017
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发表时间：
2019-07-16
期刊：
影响因子：
32.4
通讯作者：
Xiao, Tsan Sam
中科院分区：
文献类型：
--
作者：
Liu, Zhonghua;Wang, Chuanping;Xiao, Tsan Sam
Gasdermin D（GSDMD）是典型和非典型炎性体信号传导途径下游的焦亡效应分子。GSDMD被炎性半胱天冬酶切割触发寡聚化和通过其N-末端结构域的脂质结合，其组装膜孔，而其C-末端结构域结合N-末端结构域以抑制焦亡。尽管最近的进展，我们的理解的结构和功能的小鼠gasdermin A3（mGSDMA 3），GSDMD的激活和调节的分子机制仍然很差的特点。在这里，我们报告了全长鼠和人GSDMD的晶体结构，揭示了GSDMD N-末端结构域的结构，并展示了gasdermin家族成员利用其β 1-β 2环的自身抑制的独特和共同特征。破坏的分子内结构域接口增强pyroptosis，而在预测的脂质结合或寡聚化表面的突变减少细胞溶解。我们的研究提供了一个框架，了解自抑制，脂质结合，寡聚化的GSDMD通过使用重叠接口。
Gasdermin D (GSDMD) is an effector molecule for pyroptosis downstream of canonical and non-canonical inflammasome signaling pathways. Cleavage of GSDMD by inflammatory caspases triggers the oligomerization and lipid binding by its N-terminal domain, which assembles membrane pores, whereas its C-terminal domain binds the N-terminal domain to inhibit pyroptosis. Despite recent progress in our understanding of the structure and function of the murine gasdermin A3 (mGSDMA3), the molecular mechanisms of GSDMD activation and regulation remain poorly characterized. Here, we report the crystal structures of the full-length murine and human GSDMDs, which reveal the architecture of the GSDMD N-terminal domains and demonstrate distinct and common features of autoinhibition among gasdermin family members utilizing their beta 1-beta 2 loops. Disruption of the intramolecular domain interface enhanced pyroptosis, whereas mutations at the predicted lipid-binding or oligomerization surface reduced cytolysis. Our study provides a framework for understanding the autoinhibition, lipid binding, and oligomerization of GSDMD by using overlapping interfaces.