2012年6月15日,，北京生命科學(xué)研究所王曉晨實(shí)驗(yàn)室與中科院生物物理所劉迎方實(shí)驗(yàn)室合作在《Genes & Development》雜志上發(fā)表題為“Structural Study of TTR-52 Reveals the Functional Mechanisms of a Bridging Molecule in Apoptotic Cell Engulfment”的文章,。
細(xì)胞凋亡時(shí)會(huì)暴露出凋亡信號(hào)，從而誘使吞噬細(xì)胞直接或者間接的識(shí)別凋亡細(xì)胞,。在線蟲中,，TTR-52是一個(gè)由吞噬細(xì)胞分泌的橋聯(lián)分子，負(fù)責(zé)識(shí)別凋亡細(xì)胞上外翻的磷脂酰絲氨酸( PS ),，同時(shí)TTR-52也可以結(jié)合吞噬細(xì)胞上的受體CED-1,，進(jìn)而介導(dǎo)凋亡細(xì)胞的吞噬。然而,，橋聯(lián)分子在結(jié)構(gòu)和分子水平上如何識(shí)別凋亡細(xì)胞的信號(hào),，如何結(jié)合吞噬細(xì)胞上的受體以傳導(dǎo)信號(hào)仍然未知。通過晶體衍射,，我們發(fā)現(xiàn)TTR-52分子形成由7個(gè)β折疊組成的一個(gè)開放的β桶結(jié)構(gòu),， 并且形成一個(gè)背靠背的二聚體。體內(nèi)和體外的實(shí)驗(yàn)證明TTR-52的第二,，第三個(gè)環(huán)狀區(qū)域像觸手一樣結(jié)合PS,；另一方面，TTR-52利用C 端結(jié)構(gòu)域與吞噬受體CED-1結(jié)合從而介導(dǎo)吞噬,。TTR-52的結(jié)構(gòu)及功能研究揭示了了橋連分子介導(dǎo)凋亡細(xì)胞吞噬的作用機(jī)制,。
康彥勇（生物物理所），趙東風(fēng)博士(NIBS)和梁歡歡博士(生物物理所)為本文的共同第一作者,。其他作者包括劉斌博士(NIBS),，張燕博士(NIBS)和劉勤文(NIBS)。我所王曉晨博士與生物物理所劉迎芳博士為共同通訊作者,。在北京生命科學(xué)研究所的工作得到科技部和北京市政府的資助,。（生物谷Bioon.com）
doi:10.1101/gad.187815.112
PMC:
PMID:
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
