Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.

Martin DA, Zheng L, Siegel RM, Huang B, Fisher GH, Wang J, Jackson CE, Puck JM, Dale J, Straus SE, Peter ME, Krammer PH, Fesik S, Lenardo MJ
Proc Natl Acad Sci U S A. 1999 96 (8): 4552-7

PMID: 10200300 · PMCID: PMC16370 · DOI:10.1073/pnas.96.8.4552

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.

MeSH Terms (17)

Adaptor Proteins, Signal Transducing Amino Acid Substitution Apoptosis Autoimmune Diseases Binding Sites Carrier Proteins Codon, Terminator Fas-Associated Death Domain Protein fas Receptor Humans Lymphoproliferative Disorders Models, Molecular Point Mutation Protein Structure, Secondary Sequence Deletion Signal Transduction Syndrome

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