TNF receptor 1 (TNF RI; also called TNF R-p55/p60 and TNFRSF1A) is a 55 kDa type I transmembrane protein member of the TNF receptor superfamily, designated TNFRSF1A. Human TNF RI is a 455 amino acid (aa) protein that contains a 21 aa signal sequence and 190 aa ECD with a PLAD (pre-ligand assembly domain) that mediates constitutive dimer/trimer formation, followed by four CRD (cysteine-rich domains), a 23 aa transmembrane domain, and a 221 aa cytoplasmic sequence that contains a neutral sphingomyelinase activation domain and a death domain. The ECD of human TNF RI shows 70%, 69%, 80%, 80%, and 73% aa identity with mouse, rat, canine, feline and porcine TNF RI, respectively; and it shows 23% aa identity with the ECD of TNF RII. Both TNF RI and TNF RII (TNFRSF1B) are widely expressed and contain four TNF-alpha trimer-binding CRD in their ECD. However, TNF RI is thought to mediate most of the cellular effects of TNF-alpha. It is essential for proper development of lymph node germinal centers and Peyer’s patches, and for combating intracellular pathogens such as Listeria. TNF RI is also a receptor for TNF-beta /TNFSF1B (lymphotoxin-alpha ). TNF RI is stored in the Golgi and translocates to the cell surface following proinflammatory stimuli. TNF-alpha stabilizes TNF RI and induces its sequestering in lipid rafts, where it activates NF kappa B and is cleaved by ADAM-17/TACE.