Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations.
Heterozygous mutations encoding abnormal forms of the death receptor Fas dominantly interfere with Fas-induced lymphocyte apoptosis in human autoimmune lymphoproliferative syndrome. This effect, rather than depending on ligand-induced receptor oligomerization, was found to stem from ligand- independent interaction of wild-type and mutant Fas receptors through a specific region in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between variants of green fluorescent protein. These results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.
Siegel
R M
RM
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Frederiksen
J K
JK
Zacharias
D A
DA
Chan
F K
FK
Johnson
M
M
Lynch
D
D
Tsien
R Y
RY
Lenardo
M J
MJ
D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000503:physiopathology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003432:Cross-Linking Reagents; D053222:Fas Ligand Protein; D006801:Humans; D008024:Ligands; D008214:Lymphocytes / Q000166:cytology; D008232:Lymphoproliferative Disorders / Q000503:physiopathology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D013388:Succinimides; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D003432:Cross-Linking Reagents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D013388:Succinimides; D019014:fas Receptor; C035759:3,3'-dithiobis(sulfosuccinimidyl propionate)