INIBITION OF AUTOPHAGY AND APOPTOSIS BY MHV68 VBCL-2

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 所有的伽玛疱疹病毒都表达抗凋亡B细胞淋巴瘤-2(BCL-2)的同源物，以对抗宿主抗病毒防御机制对感染细胞的清除。为了深入了解这些病毒BCL-2蛋白的作用机制，我们对小鼠g疱疹病毒68的M11、病毒BCL-2与来自一系列促凋亡的BCL-2家族蛋白的前自噬Beclin1和BCL-2同源3(BH3)结构域多肽的相互作用进行了结构和生化分析。M11主要通过疏水相互作用与Beclin1的BH3样结构域结合，解离常数为44纳米摩尔，与细胞bcl2与Beclin1的1.6微摩尔结合亲和力相比明显更紧密。在NIH3T3细胞中，M11始终比bcl2更有效地抑制自噬。M11还与BAK的BH3结构域肽以及BIm、Bid、Bmf、PUMA和Noxa上游蛋白的BIm、Bid、BmF、PUMA和Noxa紧密结合，但与Bax的作用较弱。与艾滋病有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. All gamma herpesviruses express homologues of antiapoptotic B-cell lymphoma-2 (BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, viral BCL-2 of murine g-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL-2 homology 3 (BH3) domain-containing peptides derived from an array of proapoptotic BCL-2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 44 nanomole, markedly tighter affinity compared to the 1.6 micromolar binding affinity between cellular BCL-2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL-2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3-only proteins BIM, BID, BMF, PUMA and Noxa, but weakly with that of BAX. AIDS related.