Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.
Heterozygous mutations in the CD95 (APO-1/Fas) receptor occur in most individuals with autoimmune lymphoproliferative syndrome (ALPS) and dominantly interfere with apoptosis by an unknown mechanism. We show that local or global alterations in the structure of the cytoplasmic death domain from nine independent ALPS CD95 death-domain mutations result in a failure to bind the FADD/MORT1 signaling protein. Despite heterozygosity for the abnormal allele, lymphocytes from ALPS patients showed markedly decreased FADD association and a loss of caspase recruitment and activation after CD95 crosslinking. These data suggest that intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by disrupting death-domain interactions with the signaling protein FADD/MORT1.
Martin
D A
DA
Laboratory of Immunology, National Institutes of Health, Bethesda, MD 20892, USA.
Zheng
L
L
Siegel
R M
RM
Huang
B
B
Fisher
G H
GH
Wang
J
J
Jackson
C E
CE
Puck
J M
JM
Dale
J
J
Straus
S E
SE
Peter
M E
ME
Krammer
P H
PH
Fesik
S
S
Lenardo
M J
MJ
D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D018388:Codon, Terminator; D053200:Fas-Associated Death Domain Protein; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology*; D008958:Models, Molecular; D017354:Point Mutation; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D015398:Signal Transduction; D013577:Syndrome; D019014:fas Receptor / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018388:Codon, Terminator; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D019014:fas Receptor