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Defective CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative syndrome, type Ia.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1999 Apr 13; Vol. 96 (8), pp. 4552-7. - Publication Year :
- 1999
-
Abstract
- 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.
- Subjects :
- Amino Acid Substitution
Apoptosis
Binding Sites
Carrier Proteins metabolism
Codon, Terminator
Fas-Associated Death Domain Protein
Humans
Models, Molecular
Point Mutation
Protein Structure, Secondary
Sequence Deletion
Signal Transduction
Syndrome
fas Receptor chemistry
fas Receptor physiology
Adaptor Proteins, Signal Transducing
Autoimmune Diseases genetics
Autoimmune Diseases immunology
Lymphoproliferative Disorders genetics
Lymphoproliferative Disorders immunology
fas Receptor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 96
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 10200300
- Full Text :
- https://doi.org/10.1073/pnas.96.8.4552