Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment
Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment
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TTR-52 的结构研究揭示了桥接分子介导凋亡细胞吞噬的机制。
DOI：
10.1101/gad.187815.112
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发表时间：
2012-06-15
影响因子：
10.5
通讯作者：
Liu, Yingfang
中科院分区：
文献类型：
--
作者：
Kang, Yanyong;Zhao, Dongfeng;Liu, Yingfang
在凋亡过程中，专业吞噬细胞或邻近吞噬细胞直接通过吞噬细胞受体或间接通过连接死亡细胞和吞噬细胞的桥接分子来清除凋亡细胞。然而，桥联分子如何识别“吃我”的信号和吞噬细胞受体来调节吞噬仍不清楚。在这里，我们报道了秀丽线虫Ttr-52的结构和功能研究，Ttr-52是一种新近发现的桥接分子，它将凋亡细胞表面暴露的磷脂酰丝氨酸(PtdSer)连接到吞噬细胞上的CED-1受体。晶体结构研究表明，TTR-52具有开放的β-桶状结构，与PKC的α-C2结构域有一些相似之处。Ttr-52被认为是通过一种离子介导的PtdSer结合方式与PtdSer结合。深入的功能研究表明，CED-1通过其N-端EMI结构域与TTR-52结合，TTR-52 C末端的疏水区参与了这一相互作用。此外，与其他PtdSer结合区不同，Ttr-52形成二聚体，其二聚化对其在体内的功能至关重要。我们的结果揭示了桥接分子的第一个全长结构和桥接分子介导的细胞凋亡识别的机制。
During apoptosis, apoptotic cells are removed by professional phagocytes or neighboring engulfing cells either directly through phagocytic receptors or indirectly through bridging molecules that cross-link dying cells to phagocytes. However, how bridging molecules recognize "eat me" signals and phagocytic receptors to mediate engulfment remains unclear. Here, we report the structural and functional studies of Caenorhabditis elegans TTR-52, a recently identified bridging molecule that cross-links surface-exposed phosphatidylserine (PtdSer) on apoptotic cells to the CED-1 receptor on phagocytes. Crystal structure studies show that TTR-52 has an open beta-barrel-like structure with some similarities to the PKC alpha-C2 domain. TTR-52 is proposed to bind PtdSer via an "ion-mediating" PtdSer-binding mode. Intensive functional studies show that CED-1 binds TTR-52 through its N-terminal EMI domain and that the hydrophobic region of the TTR-52 C terminus is involved in this interaction. In addition, unlike other PtdSer-binding domains, TTR-52 forms dimers, and its dimerization is important for its function in vivo. Our results reveal the first full-length structure of a bridging molecule and the mechanism underlying bridging molecule-mediated apoptotic cell recognition.