sickle, a novel Drosophila death gene in the reaper/hid/grim region, encodes an IAP-inhibitory protein.
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.
Srinivasula
Srinivasa M
SM
The Center for Apoptosis Research, Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Datta
Pinaki
P
Kobayashi
Masatomo
M
Wu
Jia Wei
JW
Fujioka
Miki
M
Hegde
Ramesh
R
Zhang
ZhiJia
Z
Mukattash
Rula
R
Fernandes-Alnemri
Teresa
T
Shi
Yigong
Y
Jaynes
James B
JB
Alnemri
Emad S
ES
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
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