Structure, interactions and self-assembly of ASC-dependent inflammasomes.
Structure, interactions and self-assembly of ASC-dependent inflammasomes.
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DOI：
10.1016/j.abb.2019.05.023
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发表时间：
2019-07-30
影响因子：
3.9
通讯作者：
de Alba E
中科院分区：
文献类型：
--
作者：
de Alba E
炎性小体是一种多蛋白平台，其在存在来自感染或组织损伤的线索时组装，并触发炎症反应。炎性体组分包括检测危险信号的传感器蛋白、半胱氨酸天冬氨酸蛋白酶原1和将这些分子拴在一起的适配器ASC（包含CARD的骨化相关斑点样蛋白）。在炎性小体组装时，半胱氨酸天冬氨酸蛋白酶原1自激活并使功能性细胞因子在防御机制中仲裁。这种组装是通过死亡结构域的自缔合和蛋白质相互作用介导的。炎性小体在先天免疫中起着关键作用，其失调是许多自身免疫性疾病的罪魁祸首。深入了解炎性小体组装中涉及的因素可能有助于对抗这些疾病。本文综述了我们目前的知识，从ASC的角度炎性小体形成的生物物理方面。ASC的三维解决方案的结构和域间动力学的具体特点解释其功能在炎性小体组装。此外，审查阐述了在氨基酸水平上使用NMR技术的ASC相互作用表面的识别。最后，宏观结构形成的全长ASC和它的两个死亡结构域的研究与透射电子显微镜进行了比较的上下文中的炎性小体组装的方向性模型。
The inflammasome is a multi-protein platform that assembles upon the presence of cues derived from infection or tissue damage, and triggers the inflammatory response. Inflammasome components include sensor proteins that detect danger signals, procaspase 1 and the adapter ASC (apoptosis-associated speck-like protein containing a CARD) tethering these molecules together. Upon inflammasome assembly, procaspase 1 self-activates and renders functional cytokines to arbitrate in the defense mechanism. This assembly is mediated by self-association and protein interactions via Death Domains. The inflammasome plays a critical role in innate immunity and its dysregulation is the culprit of many autoimmune disorders. An in-depth understanding of the factors involved in inflammasome assembly could help fight these conditions. This review describes our current knowledge on the biophysical aspects of inflammasome formation from the perspective of ASC. The specific characteristics of the three-dimensional solution structure and interdomain dynamics of ASC are explained in relation to its function in inflammasome assembly. Additionally, the review elaborates on the identification of ASC interacting surfaces at the amino acid level using NMR techniques. Finally, the macrostructures formed by full-length ASC and its two Death Domains studied with Transmission Electron Microscopy are compared in the context of a directional model for inflammasome assembly.
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