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Crystal structure of caspase-11 CARD provides insights into caspase-11 activation
Cell Discovery ( IF 13.0 ) Pub Date : 2020-10-13 , DOI: 10.1038/s41421-020-00201-w
Muziying Liu , Kang Zhou , Zhihao Xu , Huan Ma , Xiaocong Cao , Xueying Yin , Weihong Zeng , Ayesha Zahid , Sicheng Fu , Kang Ni , Xiaodong Ye , Ying Zhou , Li Bai , Rongbin Zhou , Tengchuan Jin

Murine caspase-11 is the centerpiece of the non-canonical inflammasome pathway that can respond to intracellular LPS and induce pyroptosis. Caspase-11 contains two components, an N-terminal caspase recruitment domain (CARD) and a C-terminal catalytic domain. The aggregation of caspase-11 is thought to promote the auto-processing and activation of caspase-11. However, the activation mechanism of caspase-11 remains unclear. In this study, we purified the caspase-11 CARD fused to an MBP tag and found it tetramerizes in solution. Crystallographic analysis reveals an extensive hydrophobic interface formed by the H1–2 helix mediating homotypic CARD interactions. Importantly, mutations of the helix H1–2 hydrophobic residues abolished the tetramerization of MBP-tagged CARD in solution and failed to induce pyroptosis in cells. Our study provides the first evidence of the homotypic interaction mode for an inflammatory caspase by crystal model. This finding demonstrates that the tetramerization of the N-terminal CARD can promote releasing of the catalytic domain auto-inhibition, leading to the caspase-11 activation.



中文翻译:

caspase-11 CARD的晶体结构提供了caspase-11激活的见解

鼠胱天蛋白酶11是非典型的炎性体途径的核心,它可以对细胞内的LPS产生反应并诱导细胞凋亡。Caspase-11包含两个组件,一个N末端caspase募集域(CARD)和一个C末端催化域。caspase-11的聚集被认为促进caspase-11的自动加工和激活。但是,caspase-11的激活机制仍不清楚。在这项研究中,我们纯化了融合到MBP标签的caspase-11 CARD,发现它在溶液中四聚。晶体学分析表明,由H1-2螺旋介导的同型CARD相互作用形成了广泛的疏水界面。重要的是,螺旋H1-2疏水残基的突变消除了溶液中MBP标记的CARD的四聚化,并且无法诱导细胞的热解。我们的研究通过晶体模型为炎性胱天蛋白酶提供了同型相互作用模式的第一个证据。该发现表明,N末端CARD的四聚化可以促进催化域自动抑制的释放,从而导致caspase-11活化。

更新日期:2020-10-13
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