A three-dimensional model of the Fas/APO-1 molecule: cross-reactivity of anti-Fas antibodies explained by structural mimicry of antigenic sites.
Fas/APO-1 is a member of the tumor necrosis factor (TNF)/nerve growth factor receptor family. This cell surface protein, when associated with the Fas/APO-1 ligand or specific mAb, elicits an apoptotic response in susceptible cells via an oligomerization of its intracellular domains, termed the'death domains'. We have previously mapped the epitopes of a panel of Fas/APO-1-reactive mAb to a series of linear portions of the Fas/APO-1 molecule. In order to gain a greater understanding of the mode of interaction of these antibodies with the Fas/APO-1 antigen, we constructed a homology-based model of the extracellular portion of the molecule, based on the crystallographic coordinates of the TNF type I receptor. The model clearly demonstrates that the antibodies do not identically mimic the endogenous ligand to achieve their effect, but probably act in an analogous manner by recruiting Fas/APO-1 molecules into clusters which may lead to oligomerization of 'death domains'. Moreover, the apparent cross-reactivity observed for the monoclonal anti-Fas antibodies between different linear regions of the Fas/APO-1 molecule was found to be due, most likely, to the structural mimicry of these epitopes. Reduction of the Fas/APO-1-derived cross-reactive peptides by dithiothreitol completely abrogated their antigenic reactivity with the anti-Fas mAb CH-11, thus indicating that the establishment of intrapeptide disulfide bonds is critical for antigenic reactivity.
Fadeel
B
B
Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
Lindberg
J
J
Achour
A
A
Chiodi
F
F
D000595:Amino Acid Sequence; D015703:Antigens, CD / Q000737:chemistry; D017209:Apoptosis; D003198:Computer Simulation; D003545:Cysteine / Q000737:chemistry; D018604:Epitope Mapping; D053222:Fas Ligand Protein; D006801:Humans; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000648:ultrastructure; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology; D011487:Protein Conformation; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry; D047888:Receptors, Tumor Necrosis Factor, Type I; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D019014:fas Receptor / Q000378:metabolism / Q000648:ultrastructure*
D015703:Antigens, CD; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D010455:Peptides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D019014:fas Receptor; D003545:Cysteine