A Mutational Analysis of the Baculovirus Inhibitor of Apoptosis Op-IAP*
A Mutational Analysis of the Baculovirus Inhibitor of Apoptosis Op-IAP*
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DOI：
10.1074/jbc.273.51.33915
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发表时间：
1998-12
期刊：
影响因子：
--
通讯作者：
D. Vučić;W. Kaiser;L. Miller
中科院分区：
文献类型：
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作者：
D. Vučić;W. Kaiser;L. Miller
一个家族的抗凋亡调节剂称为细胞凋亡抑制剂（IAP）最初确定和功能描述的杆状病毒，IAP同源物是现在已知的昆虫，鸟类和哺乳动物。杆状病毒和果蝇IAP抑制果蝇促凋亡蛋白Reaper、HID和GRIM诱导的细胞凋亡，并通过杆状病毒IAP重复序列（BIR）与它们发生物理相互作用。在这里，我们研究了BIR和环指基序的Orgyia pseudotsugata核型多角体病毒Op-IAP和D-IAP 1在结合和抑制HID的功能的重要性。在缺乏BIR 1和RING基序的情况下，Op-IAP和D-IAP 1的BIR 2区域能够与HID相关并阻断HID诱导的细胞凋亡。BIR和RING指基序内保守氨基酸残基的突变揭示了BIR 2内的保守残基对于Op-IAP抑制凋亡是必需的。然而，BIR 2的大多数保守残基对于HID结合不是必需的。在BIR 2的羧基近端的区域是必不可少的协会的Op-IAP与HID。因此，与HID的结合是必要的，但不足以阻断HID诱导的细胞凋亡：BIR 2内的保守残基必须在阻断细胞凋亡中发挥额外的作用。这些发现表明，包含Op-IAP和D-IAP 1的单个BIR的区域足以与HID诱导的细胞凋亡发生物理相互作用并抑制HID诱导的细胞凋亡。
A family of antiapoptotic regulators known as inhibitors of apoptosis (IAPs) was initially identified and functionally described in baculoviruses, and IAP homologues are now known in insects, birds, and mammals. Baculovirus andDrosophila IAPs inhibit apoptosis induced byDrosophila proapoptotic proteins Reaper, HID, and GRIM and physically interact with them through their baculovirus IAP repeat (BIR) region. Here we examined the functional importance of BIR and RING finger motifs of Orgyia pseudotsugata nuclear polyhedrosis virus Op-IAP and D-IAP1 in binding to and inhibiting HID. In the absence of both the BIR1 and RING motifs, the BIR2 regions of Op-IAP and D-IAP1 were able to associate with HID and block HID-induced apoptosis. Mutation of conserved amino acid residues within the BIR and RING finger motifs revealed that the conserved residues within BIR2 were essential for Op-IAP to inhibit apoptosis. However, most of the conserved residues of the BIR2 were not required for HID binding. A region at the carboxy-proximal end of BIR2 was essential for the association of Op-IAP with HID. Thus binding to HID is necessary but not sufficient to block HID-induced apoptosis: the conserved residues within BIR2 must have an additional role in blocking apoptosis. These findings demonstrate that the region encompassing a single BIR of Op-IAP and D-IAP1 can be sufficient for physical interaction with and inhibition of apoptosis induced by HID.