A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways
A peptide inhibitor of cytochrome c/inositol 1,4,5-trisphosphate receptor binding blocks intrinsic and extrinsic cell death pathways
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DOI：
10.1073/pnas.0409650102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Snyder, SH
中科院分区：
文献类型：
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作者：
Boehning, D;van Rossum, DB;Snyder, SH
凋亡刺激通过内质网钙库上的肌醇1，4，5-三磷酸受体（IP 3R）增加细胞内钙浓度。我们以前发现了一个凋亡级联反应，其中细胞色素c在凋亡早期与IP（3）R结合，导致钙释放失调。在这里，我们表明，细胞色素c结合IP 3R依赖于一个集群的谷氨酸残基内的C末端的通道。衍生自该序列的细胞渗透肽从IP 3R置换细胞色素c并消除由星形孢菌素处理HeLa细胞和Fas配体刺激Jurkat细胞诱导的细胞死亡。细胞色素c/IP 3R相互作用的小分子抑制剂可能被证明可用于治疗与不适当的内在和外在凋亡信号相关的疾病。
Apoptotic stimuli augment intracellular calcium concentration through inositol 1,4,5-trisphosphate receptors (IP3R) on endoplasmic reticulum calcium stores. We previously discovered an apoptotic cascade wherein cytochrome c binds to lP(3)R early in apoptosis, resulting in dysregulated calcium release. Here we show that cytochrome c binding to lP3R depends on a cluster of glutamic acid residues within the C terminus of the channel. A cell permeant peptide derived from this sequence displaces cytochrome c from IP3R and abrogates cell death induced by staurosporine treatment of HeLa cells and Fas ligand stimulation of Jurkat cells. Small-molecule inhibitors of cytochrome c/IP3R interactions may prove useful in treating disorders associated with inappropriate intrinsic and extrinsic apoptotic signaling.