Characterization of the non-functional Fas ligand of gld mice

Mice homozygous for either the gld or Ipr mutation develop autoimmunediseases and progressive lymphadenopathy. The Ipr mutation Ischaracterized by the absence of unctional Fas, whereas gld miceexhibit an inactive FasL due to a point mutation proximal tothe extracellular C-terminus. The structural repercussions ofthis amino acid substitution remain unknown. Here we reportthat FasL Is expressed at similar levels on the surface of activatedT lymphocytes from gld and wild-type mice. Using a polyclonalanti-FasL antibody, Indistinguishable amounts of a 40 kDa proteinare detected In both gld and wild-type splenocytes. The molecularmodel of FasL, based on the known structure of TNF-, predictsthat the PheLeu gld mutation is located at the protomer interfacewhich Is close to the FasR Interaction site. We conclude thatthe gld mutation allows normal FasL biosynthesis, surface expressionand ollgomerlzatlon, but induces structural alterations to theFas binding region leading to the phenotypic changes observed.