Srivastava M, Scherr H, Lackey M, Xu D, Chen Z, Lu J, Bergmann A
Department of Biochemistry and Molecular Biology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Cell Death Differ. 2007 Jan;14(1):92-102. doi: 10.1038/sj.cdd.4401931. Epub 2006 Apr 28.
In mammals and Drosophila, apoptotic caspases are under positive control of the CED-4-like proteins Apaf-1 and ARK, respectively. In an EMS-mutagenesis screen, we isolated 33 ark mutants as recessive suppressors of hid-induced apoptosis. The ark mutants are loss-of-function alleles characterized by reduced developmental apoptosis. Using the phenotypic series of these alleles, we identified helical domain I in the nucleotide oligomerization domain as critical for ARK's apoptotic activity. Interestingly, the WD40 region may also have an unanticipated positive requirement for the apoptotic activity of ARK. Considering structural information, we discuss the roles of these domains for assembly and activity of the ARK apoptosome, and propose that the WD40 region is anti-apoptotic in the absence of apoptotic signals, and pro-apoptotic in the presence of such signals. Furthermore, a defined null allele reveals that ark is required for most, but not all apoptosis suggesting the existence of an ARK-independent apoptotic pathway.
在哺乳动物和果蝇中，凋亡性半胱天冬酶分别受CED-4样蛋白Apaf-1和ARK的正向调控。在一项EMS诱变筛选中，我们分离出33个ark突变体，作为hid诱导凋亡的隐性抑制子。ark突变体是功能缺失等位基因，其特征是发育性凋亡减少。利用这些等位基因的表型系列，我们确定核苷酸寡聚化结构域中的螺旋结构域I对ARK的凋亡活性至关重要。有趣的是，WD40区域对ARK的凋亡活性可能也有出人意料的正向需求。考虑到结构信息，我们讨论了这些结构域对ARK凋亡小体组装和活性的作用，并提出WD40区域在没有凋亡信号时具有抗凋亡作用，而在有此类信号时具有促凋亡作用。此外，一个明确的无效等位基因表明，大多数（但不是所有）凋亡都需要ark，这表明存在一条不依赖ARK的凋亡途径。
