MAPPING OF THE LINEAR SITE ON THE FAS APO-1 MOLECULE TARGETED BY THE PROTOTYPIC ANTI-FAS MAB/

Fas/APO-1 is a member of the nerve growth factor/tumor necrosis factor (TNF) family of receptors and has been shown to mediate apoptotic cel l death upon binding of specific mAb. We report here that the prototyp ic anti-human Fas mAb (clone CH-11) induces apoptosis by binding to a linear epitope present on the extracellular domain of the Fas/APO-1 pr otein. Synthetic peptides corresponding to this epitope blocked the ap optotic effect of the antibody in a susceptible Jurkat T cell line. Ba sed upon the similarity between the Fas/APO-1 protein and the recently crystallized soluble TNF receptor type I, we generated a molecular mo del of Fas/APO-1. Our computer modeling indicates that the antibody bi nding region forms a hairpin loop on the surface of the Fas/APO-1 prot ein. These findings further our understanding of the Fas/APO-1-mediate d apoptotic signal and may provide a useful tool in future investigati ons of programmed cell death.