Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations

Heterozygous mutations encoding abnormal forms of the death receptor Fas do minantly interfere with Fas-induced Lymphocyte apoptosis in human autoimmun e Lymphoproliferative syndrome. This effect, rather than depending on ligan d-induced receptor oligomerization, was found to stem from ligand-independe nt interaction of wild-type and mutant Fas receptors through a specific reg ion in the extracellular domain. Preassociated Fas complexes were found in living cells by means of fluorescence resonance energy transfer between var iants of green fluorescent protein. These results show that formation of pr eassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.