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首页> 外文期刊>Journal of Molecular Biology >Crystal structure of the F27G AIM2 PYD mutant and similarities of its self-association to DED/DED interactions.
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Crystal structure of the F27G AIM2 PYD mutant and similarities of its self-association to DED/DED interactions.

机译：F27G AIM2 PYD突变体的晶体结构及其与DED / DED相互作用的自相关性相似。

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摘要

Absent in melanoma 2 (AIM2) is a cytoplasmic double-stranded DNA sensor involved in innate immunity. It uses its C-terminal HIN domain for recognizing double-stranded DNA and its N-terminal pyrin domain (PYD) for eliciting downstream effects through recruitment and activation of apoptosis-associated Speck-like protein containing CARD (ASC). ASC in turn recruits caspase-1 and/or caspase-11 to form the AIM2 inflammasome. The activated caspases process proinflammatory cytokines IL-1β and IL-18 and induce the inflammatory form of cell death pyroptosis. Here we show that AIM PYD (AIM2(PYD)) self-oligomerizes. We notice significant sequence homology of AIM2(PYD) with the hydrophobic patches of death effector domain (DED)-containing proteins and confirm that mutations on these residues disrupt AIM2(PYD) self-association. The crystal structure at 1.82? resolution of such a mutant, F27G of AIM2(PYD), shows the canonical six-helix (H1-H6) bundle fold in the death domain superfamily. In contrast to the wild-type AIM2(PYD) structure crystallized in fusion with the large maltose-binding protein tag, the H2-H3 region of the AIM2(PYD) F27G is well defined with low B-factors. Structural analysis shows that the conserved hydrophobic patches engage in a type I interaction that has been observed in DED/DED and other death domain superfamily interactions. While previous mutagenesis studies of PYDs point to the involvement of charged interactions, our results reveal the importance of hydrophobic interactions in the same interfaces. These centrally localized hydrophobic residues within fairly charged patches may form the hot spots in AIM2(PYD) self-association and may represent a common mode of PYD/PYD interactions in general.
机译：黑色素瘤2（AIM2）缺失是涉及先天免疫的细胞质双链DNA传感器。它利用其C末端的HIN域识别双链DNA，并利用其N末端的吡啶结构域（PYD）通过募集和激活与细胞凋亡相关的含有斑点的蛋白质样CARD（ASC）来引发下游效应。 ASC反过来募集caspase-1和/或caspase-11以形成AIM2炎性小体。活化的半胱天冬酶处理促炎细胞因子IL-1β和IL-18，并诱导炎性形式的细胞死亡凋亡。在这里，我们显示AIM PYD（AIM2（PYD））自聚。我们注意到具有死亡效应域（DED）的蛋白质的疏水补丁的AIM2（PYD）的重要序列同源性，并确认这些残基上的突变破坏了AIM2（PYD）的自缔合。晶体结构在1.82？这种突变体AIM2（PYD）的F27G的解析显示了死亡域超家族中的规范六螺旋（H1-H6）束折叠。与与大麦芽糖结合蛋白标签融合而结晶的野生型AIM2（PYD）结构相反，AIM2（PYD）F27G的H2-H3区定义良好，且B因子较低。结构分析表明，保守的疏水补丁参与了DED / DED和其他死亡域超家族相互作用中观察到的I型相互作用。虽然以前的PYD诱变研究指出了带电相互作用的参与，但我们的结果揭示了在相同界面上疏水性相互作用的重要性。这些在带正电电荷的贴片中居中定位的疏水性残基可能会形成AIM2（PYD）自缔合中的热点，并且通常代表PYD / PYD相互作用的常见模式。

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