tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.
tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.
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DOI：
10.1101/gad.14.16.2060
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发表时间：
2000-08
影响因子：
10.5
通讯作者：
M. Wei;T. Lindsten;V. Mootha;S. Weiler;A. Gross;M. Ashiya;C. Thompson;S. Korsmeyer
中科院分区：
文献类型：
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作者：
M. Wei;T. Lindsten;V. Mootha;S. Weiler;A. Gross;M. Ashiya;C. Thompson;S. Korsmeyer
TNFR 1/Fas接合导致胞质BID裂解为截短的tBID，其易位至线粒体。免疫耗竭和基因破坏表明细胞色素c释放需要BID。令人惊讶的是，这个只有BH 3结构域的分子的三维结构显示了两个疏水性α-螺旋，这表明tBID本身可能是一种成孔蛋白。相反，我们证明，tBID功能作为一个膜靶向的死亡配体，其中一个完整的BH 3结构域是细胞色素c释放所需的，但不是针对。Bak缺陷的线粒体和阻断抗体揭示tBID结合其线粒体伴侣巴克释放细胞色素c，这是一个独立于渗透性转变的过程。活化的tBID导致巴克的变构活化，诱导其膜内寡聚化进入细胞色素c流出的拟议孔，整合从死亡受体到细胞死亡的途径。
TNFR1/Fas engagement results in the cleavage of cytosolic BID to truncated tBID, which translocates to mitochondria. Immunodepletion and gene disruption indicate BID is required for cytochrome c release. Surprisingly, the three-dimensional structure of this BH3 domain-only molecule revealed two hydrophobic alpha-helices suggesting tBID itself might be a pore-forming protein. Instead, we demonstrate that tBID functions as a membrane-targeted death ligand in which an intact BH3 domain is required for cytochrome c release, but not for targeting. Bak-deficient mitochondria and blocking antibodies reveal tBID binds to its mitochondrial partner BAK to release cytochrome c, a process independent of permeability transition. Activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux, integrating the pathway from death receptors to cell demise.