International Immunology, Vol 10, 131-140, Copyright © 1998 by Oxford University Press
B Fadeel, J Lindberg, A Achour and F Chiodi
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.
ARTICLES
A three-dimensional model of the Fas/APO-1 molecule: cross-reactivity of anti-Fas antibodies explained by structural mimicry of antigenic sites
Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden.
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