INIBITION OF AUTOPHAGY AND APOPTOSIS BY MHV68 VBCL-2

MHV68 VBCL-2 对自噬和细胞凋亡的抑制

• 批准号: 7715516
• 负责人: Bonsu Ku
• 金额: $ 3.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715516
• 关键词: Acquired Immunodeficiency Syndrome; Affinity; Antiviral Agents; Apoptosis; Autophagocytosis; B-Cell Lymphomas; BAK1 gene; BAX gene; BIM Bcl-2-binding protein; Bax protein; Binding; Biochemical; Cells; Computer Retrieval of Information on Scientific Projects Database; Dissociation; Funding; Grant; Herpesviridae; Homologous Gene; Hydrophobic Interactions; Institution; Mus; Noxae; Peptides; Protein Family; Proteins; Research; Research Personnel; Resources; Simplexvirus; Source; Tertiary Protein Structure; United States National Institutes of Health; Viral; insight

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 所有γ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，我们进行了结构和生化分析的相互作用M11，病毒BCL-2的小鼠G-疱疹病毒68，与一个片段的proautophagic Beclin 1和BCL-2同源3（BH 3）域含有肽衍生自一系列的促凋亡BCL-2家族蛋白。M11主要通过疏水相互作用结合Beclin 1的BH 3样结构域，解离常数为44纳摩尔，与细胞BCL-2和Beclin 1之间的1.6微摩尔结合亲和力相比，亲和力明显更强。M11对NIH 3 T3细胞自噬的抑制作用强于BCL-2。M11还与巴克的BH 3结构域肽以及上游的仅含BH 3的蛋白BIM、BID、BMF、Noxa和Noxa的BH 3结构域肽紧密结合，但与BAX的BH 3结构域肽弱结合。艾滋病相关