Mechanisms of Gasdermin Recognition by Proteases.
Mechanisms of Gasdermin Recognition by Proteases.
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DOI：
10.1016/j.jmb.2021.167274
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发表时间：
2022-02-28
影响因子：
5.6
通讯作者：
Xiao TS
中科院分区：
文献类型：
--
作者：
Liu Z;Busscher BM;Storl-Desmond M;Xiao TS
gasdermin家族的成员含有能够结合磷脂和组装膜孔的带正电荷的N-末端结构域（NTD），以及结合NTD以防止静息状态下孔形成的C-末端结构域（CTD）。gasdermin的柔性NTD-CTD接头区在长度和序列上高度可变，这可能归因于gasdermin被不同蛋白酶识别。此外，已知NTD内的蛋白酶切割会破坏几个gasdermin家族成员。不同蛋白酶对gasdermin家族成员的识别和切割在蛋白酶活性位点以及最近鉴定为炎性半胱天冬酶的外切位点处具有共同和独特的特征。利用外切位点可以加强酶与底物的相互作用，提高蛋白质水解效率，增强底物选择性。尚待确定的是，炎性半胱天冬酶对gasdermin D（GSDMD）的双位点识别是否被其他GSDMD靶向蛋白酶所利用，或者是否参与其他gasdermin的蛋白水解加工。生物化学和结构的方法将有助于揭示如何在不同的蛋白酶潜在的外切位点从事不同的gasdermin基板。gasdermin序列、结构、表达特征和翻译后修饰的不同特征可能决定了蛋白酶依赖性激活或失活的不同机制。这些不同的机制可能是gasdermins不同的生理和病理功能的基础，并为gasdermins在感染性疾病和炎症性疾病中的治疗靶向提供了机会。
Members of the gasdermin family contain positively charged N-terminal domains (NTDs) capable of binding phospholipids and assembling membrane pores, and C-terminal domains (CTDs) that bind the NTDs to prevent pore formation in the resting states. The flexible NTD-CTD linker regions of gasdermins are highly variable in length and sequences, which may be attributable to gasdermin recognition by diverse proteases. In addition, protease cleavage within the NTDs is known to inactivate several gasdermin family members. Recognition and cleavage of the gasdermin family members by different proteases share common and distinct features at the protease active sites, as well as exosites recently identified for the inflammatory caspases. Utilization of exosites may strengthen enzyme-substrate interaction, improve efficiency of proteolysis, and enhance substrate selectivity. It remains to be determined if the dual site recognition of gasdermin D (GSDMD) by the inflammatory caspases is employed by other GSDMD-targeting proteases, or is involved in proteolytic processing of other gasdermins. Biochemical and structural approaches will be instrumental in revealing how potential exosites in diverse proteases engage different gasdermin substrates. Different features of gasdermin sequence, structure, expression characteristics, and post-translational modifications may dictate distinct mechanisms of protease-dependent activation or inactivation. Such diverse mechanisms may underlie the divergent physiological and pathological functions of gasdermins, and furnish opportunities for therapeutic targeting of gasdermins in infectious diseases and inflammatory disorders.
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影响因子：
3.7
作者：
Jabaiah, Abeer M.;Getz, Jennifer A.;Daugherty, Patrick S.
通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
24.8
作者：
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DOI：
10.1038/nsb945
发表时间：
2003-07-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Hink-Schauer, C;Estébanez-Perpiná, E;Jenne, DE
通讯作者：
Jenne, DE