Identification and characterization of a ligand-independent oligomerization domain in the extracellular region of the CD95 death receptor.
The CD95 death receptor plays an important role in several physiological and pathological apoptotic processes involving in particular the immune system. CD95 ligation leads to clustering of the receptor cytoplasmic "death domains" and recruitment of the zymogen form of caspase-8 to the cell surface. Activation of this protease through self-cleavage, followed by activation of downstream effector caspases, culminates in cleavage of a set of cellular proteins resulting in apoptosis with disassembly of the cell. It is very well known that the extracellular region of the CD95 receptor is required for CD95L interaction and that the death domain is necessary for the induction of the apoptotic signaling. Here, we identified and characterized a novel CD95 ligand- and death domain-independent oligomerization domain mapping to the NH(2)-terminal extracellular region of the CD95 receptor. In vitro and in vivo studies indicated that this domain, conserved among all soluble CD95 variants, mediates homo-oligomerization of the CD95 receptor and of the soluble CD95 proteins, as well as hetero-oligomerization of the receptor with the soluble variants. These results offer new insight into the mechanism of apoptosis inhibition mediated by the soluble CD95 proteins and suggest a role of the extracellular oligomerization domain in the regulation of the non-signaling state of the CD95 receptor.
Papoff
G
G
Institute of Cell Biology, National Research Council, Campus "Adriano Buzzati-Traverso," Via E. Ramarini 32, 00016 Monterotondo Scalo, Rome, Italy.
Hausler
P
P
Eramo
A
A
Pagano
M G
MG
Di Leve
G
G
Signore
A
A
Ruberti
G
G
D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D001704:Biopolymers; D002460:Cell Line; D002850:Chromatography, Gel; D017931:DNA Primers; D006801:Humans; D007457:Iodine Radioisotopes; D008024:Ligands; D011233:Precipitin Tests; D015398:Signal Transduction; D020798:Two-Hybrid System Techniques; D019014:fas Receptor / Q000737:chemistry / Q000378:metabolism*
D001704:Biopolymers; D017931:DNA Primers; D007457:Iodine Radioisotopes; D008024:Ligands; D019014:fas Receptor