title: sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein.
abstract: Inhibitors of apoptosis proteins (IAPs) interact with caspases and inhibit their protease activity, whereas the IAP-inhibitory proteins Smac/DIABLO in mammals and Reaper, Hid, and Grim in flies relieve IAP-mediated inhibition to induce cell death. Here we describe the functional characterization of the novel Drosophila cell death protein Sickle (Skl), which binds to IAPs and neutralizes their apoptotic inhibitory activity. Skl exhibits no sequence homology to Reaper, Hid, Grim, or Smac/DIABLO, except within the 4 residue N-terminal IAP binding motif. Skl interacts with Drosophila and mammalian IAPs and can promote caspase activation in the presence of IAPs. Consistent with these findings, expression of Skl in Drosophila and mammalian cell lines or in Drosophila embryos induces apoptosis. Skl can also synergize with Grim to induce cell death in the Drosophila eye imaginal disc. Based on biochemical and structural data, the N terminus of Skl, like that of the mammalian Smac/DIABLO, is absolutely required for its apoptotic and caspase-promoting activities and its ability to interact with IAPs. These findings point to conservation in the structure and function of the IAP-inhibitory proteins across species and suggest the existence of other family members.
authors.affiliation: The Center for Apoptosis Research, Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
authors.forename: Pinaki
authors.initials: P
authors.lastname: Datta
authors.forename: Masatomo
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Jia Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: Miki
authors.initials: M
authors.lastname: Fujioka
authors.forename: Ramesh
authors.initials: R
authors.lastname: Hegde
authors.forename: ZhiJia
authors.initials: Z
authors.lastname: Zhang
authors.forename: Rula
authors.initials: R
authors.lastname: Mukattash
authors.forename: Teresa
authors.initials: T
authors.lastname: Fernandes-Alnemri
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.forename: James B
authors.initials: JB
authors.lastname: Jaynes
authors.forename: Emad S
authors.initials: ES
authors.lastname: Alnemri
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004330:Drosophila / Q000196:embryology / Q000235:genetics*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics; D010455:Peptides / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D019476:Insect Proteins; D009479:Neuropeptides; D010455:Peptides; C108881:grim protein, Drosophila; C086973:rpr protein, Drosophila; C452430:skl protein, Drosophila