NMR STRUCTURE AND MUTAGENESIS OF THE FAS (APO-1 CD95) DEATH DOMAIN/

PROGRAMMED cell death (apoptosis) mediated by the cytokine receptor Fa s is critical for the removal of autoreactive T cells(1), the mechanis m of immune privilege(2,3), and for maintenance of immune-system homeo stasis(4). Signalling of programmed cell death involves the self-assoc iation of a conserved cytoplasmic region of Fas called the death domai n(5-7) and interaction with another death-domain-containing protein, F ADD(8) (also known as MORT1)(9). Although death domains are found in s everal proteins(10), their three dimensional structure and the manner in which they interact is unknown, Here we describe the solution struc ture of the Fas death domain, as determined by NMR spectroscopy, The s tructure consists of six antiparallel, amphipathic a-helices arranged in a novel fold, From the structure and from site-directed mutagenesis , we have identified the region of the death domain involved in self-a ssociation and binding to the downstream signalling partner FADD.