美国凯斯西储大学Tsan Sam Xiao课题组解析出胱天蛋白酶-1与Gasdermin D（GSDMD）发生相互作用的结构基础。2020年6月17日，《免疫》在线发表了这一成果。

研究人员报道了人类胱天蛋白酶-1和全长小鼠GSDMD复合物的晶体结构。 除了胱天蛋白酶-1活性位点与GSDMD N和C结构域连接子接合外，胱天蛋白酶-1 L2和L2'环上的反平行β折叠还结合了GSDMD C末端结构域的疏水口袋。该“外位点”界面除了具有自抑制作用外，还为GSDMD C末端结构域提供了一个额外的功能，即胱天蛋白酶招募模块。

因此，这项研究揭示了胱天蛋白酶-1与GSDMD的双界面结合，这可能适用于胱天蛋白酶的其他生理底物。

据了解，炎症胱天蛋白酶-1、4、5和11对GSDMD的识别和切割是在炎性体活化后启动细胞焦亡的重要步骤。先前的工作已经确定了底物（例如GSDMD）中的切割位点特征，但尚不清楚这些是否是胱天蛋白酶参与的唯一决定因素。

附：英文原文

Title: Caspase-1 Engages Full-Length Gasdermin D through Two Distinct Interfaces That Mediate Caspase Recruitment and Substrate Cleavage

Author: Zhonghua Liu, Chuanping Wang, Jie Yang, Yinghua Chen, Bowen Zhou, Derek W. Abbott, Tsan Sam Xiao

Issue&Volume: 2020-06-17

Abstract: The recognition and cleavage of gasdermin D (GSDMD) by inflammatory caspases-1, 4,5, and 11 are essential steps in initiating pyroptosis after inflammasome activation.Previous work has identified cleavage site signatures in substrates such as GSDMD,but it is unclear whether these are the sole determinants for caspase engagement.Here we report the crystal structure of a complex between human caspase-1 and thefull-length murine GSDMD. In addition to engagement of the GSDMD N- and C-domain linkerby the caspase-1 active site, an anti-parallel β sheet at the caspase-1 L2 and L2′loops bound a hydrophobic pocket within the GSDMD C-terminal domain distal to itsN-terminal domain. This “exosite” interface endows an additional function for theGSDMD C-terminal domain as a caspase-recruitment module besides its role in autoinhibition.Our study thus reveals dual-interface engagement of GSDMD by caspase-1, which maybe applicable to other physiological substrates of caspases.

DOI: 10.1016/j.immuni.2020.06.007

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30237-5