TNF Superfamily Ligands

There are currently 19 TNF superfamily ligands. Most TNF ligands are type II transmembrane proteins whose extracellular domains can be cleaved by specific metalloproteinases to generate soluble cytokines. Cleaved and non-cleaved ligands are active as non-covalent homotrimers except for Lymphotoxin beta, which forms heterotrimers with TNF-beta and BAFF, which forms heterotrimers with APRIL. TNF family ligands are characterized by a stalk of varying length connecting the transmembrane domain to the core region, which contains the hallmark structure of TNF family ligands, the TNF homology domain (THD). The THD is an anti-parallel beta-pleated sheet sandwich with a "jelly-roll" topology. Conserved residues within the beta-strands provide specific inter-subunit contacts, which stabilize the trimeric structure. Sequences in the loops connecting adjacent beta-strands are family member-specific and are important for conferring receptor specificity.