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標題: 先天性免疫系統內偵測c-di-GMP分子 之STING蛋白結構及功能分析
Structural and functional analysis of c-di-GMP detection by an innate immune adaptor protein STING
作者: 蘇義哲
Su, Yi-Che
關鍵字: 環狀二鳥甘酸;c-di-GMP;干擾素刺激因子;先天性免疫系統;STING;innate immune system
出版社: 生命科學系所
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哺乳類動物細胞內質網上的膜蛋白STING(stimulators of IFN genes,亦被稱作 MITA,ERIS,MPYS或是TMEM173)被認為是能在細胞內偵測外源性雙股DNA的一個adapter蛋白,且能進一步活化TANK binding kinase 1 (TBK1) 及其下游的轉錄因子IFN-regulator factor 3 (IRF3)。近來研究指出STING蛋白本身能直接與細菌的c-di-GMP分子結合,且近來好幾個人類的STING C-Terminal domain (hSTING-CTD)二聚體及hSTING-CTD-c-di-GMP的複合體結構已被解析報導,但都為開放式 (open)構型。在本研究中我們利用X-ray的晶體繞射技術解析,不同結晶條件下所得到的murine STING-CTD (mSTING138-344)蛋白晶體,分別得到了封閉式 (closed)-unliganded構型的二聚體結構及封閉式 (closed)-liganded構型的複合體結構。在這兩個closed構型的結構中,其複合體結構間的胺基酸有許多的交互作用,並且藉由π-helix來和c-di-GMP分子結合。本報告亦發現mSTING-CTD-c-di-GMP 複合體結構共結合了三個c-di-GMP分子。在第一個結合區中,一個c-di-GMP分子深埋於mSTING-CTD二聚體的interface間並與不同的胺基酸殘基呈現不對稱的結合。在第二個結合區中,則有兩個c-di-GMP分子以對稱性方式結合於α7 helix-α8 helix間的 loop區域周圍且部份暴露於水溶液中。mSTING-CTD二聚體具有兩種c-di-GMP結合區,能藉由isothermal calorimeter (ITC)的數據清楚證明,且與先前in vivo mSTING點突變的研究報告有一致的結果。完整的unliganded及liganded的STING-CTD及STING-CTD-c-di-GMP結構及功能上的研究,允許我們推測STING-CTD與c-di-GMP分子一個更完整的結合作用方式,這包括了兩個少見的open-liganded和closed-unliganded的STING-CTD結構。

The mammalian ER protein STING (stimulators of IFN genes; also known as MITA, ERIS, MPYS and TMEM173) is an adaptor protein linking detection of cytosolic dsDNA to activation of TANK binding kinase 1 (TBK1) and its downstream transcription factor IFN-regulator factor 3 (IRF3). Recently, STING itself was found to be the direct binder of bacterial c-di-GMP, and crystal structures of several human STING C-Terminal domain (hSTING-CTD) dimer in its apo-form or complex-form with c-di-GMP, representing the open-unliganded or open-liganded forms, respectively, have been reported. Here we report an alternate set of murine STING-CTD (mSTING137-344) structures, which were determined from crystals obtained in different conditions, and correspond to its closed-unliganded and closed-liganded forms. These two closed-forms exhibit extensive interactions between the two monomers or with the c-di-GMP ligands via the help of a kinked π-helix. In addition, three c-di-GMP molecules are found in each mSTING137-344 dimer, with one c-di-GMP buried deeply in the dimeric interface with marked asymmetry, and other two c-di-GMP bound symmetrically at the peripheral α7 helix-α8 helix loop region and partially exposed to solvent. The two c-di-GMP binding sites are clearly revealed by isothermal calorimeter (ITC) method and are consistent with the previous in vitro and in vivo biochemical studies. Detailed structural and functional studies of the unliganded- and liganded-forms of the STING-CTD protein and STING-CTD-c-di-GMP complex enable us to propose a more comprehensive STING-c-di-GMP interaction scheme that incorporates the two rarely detected open-liganded and closed-unliganded STING-CTD structures.
其他識別: U0005-0808201219064500
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