2012年6月15日，北京生命科学研究所王晓晨实验室与中科院生物物理所刘迎方实验室合作在《Genes & Development》杂志上发表题为“Structural Study of TTR-52 Reveals the Functional Mechanisms of a Bridging Molecule in Apoptotic Cell Engulfment”的文章。
细胞凋亡时会暴露出凋亡信号，从而诱使吞噬细胞直接或者间接的识别凋亡细胞。在线虫中，TTR-52是一个由吞噬细胞分泌的桥联分子，负责识别凋亡细胞上外翻的磷脂酰丝氨酸( PS )，同时TTR-52也可以结合吞噬细胞上的受体CED-1，进而介导凋亡细胞的吞噬。然而，桥联分子在结构和分子水平上如何识别凋亡细胞的信号，如何结合吞噬细胞上的受体以传导信号仍然未知。通过晶体衍射，我们发现TTR-52分子形成由7个β折叠组成的一个开放的β桶结构， 并且形成一个背靠背的二聚体。体内和体外的实验证明TTR-52的第二，第三个环状区域像触手一样结合PS；另一方面，TTR-52利用C 端结构域与吞噬受体CED-1结合从而介导吞噬。TTR-52的结构及功能研究揭示了了桥连分子介导凋亡细胞吞噬的作用机制。
康彦勇（生物物理所），赵东风博士(NIBS)和梁欢欢博士(生物物理所)为本文的共同第一作者。其他作者包括刘斌博士(NIBS)，张燕博士(NIBS)和刘勤文(NIBS)。我所王晓晨博士与生物物理所刘迎芳博士为共同通讯作者。在北京生命科学研究所的工作得到科技部和北京市政府的资助。（生物谷Bioon.com）
doi:10.1101/gad.187815.112
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Structural study of TTR-52 reveals the mechanism by which a bridging molecule mediates apoptotic cell engulfment
Yanyong Kang1,3, Dongfeng Zhao2,3, Huanhuan Liang1,3, Bin Liu2, Yan Zhang2, Qinwen Liu2, Xiaochen Wang2,4 and Yingfang Liu1,4
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 β-barrel-like structure with some similarities to the PKCα-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
