Receptor Family

During a typical immune reaction, lymphocytes respond to the antigen challenge, multiply, and die in rapid succession. Regulation of lymphocyte demise is of critical importance considering their fast multiplication after the initial challenge. Lymphocyte demise is initiated by the activation of death-inducing molecules such as the tumour necrosis factor (TNF) receptors and withdrawal of cytokines. The death domain is a key element in signal transduction TNF receptors are single transmembrane proteins characterized by an extracellular region with two or more cysteine-rich domains arranged as cystine knots. On the basis of the presence or absence of the intracellular death domain (DD), TNF receptors fall into two classes. This domain of 70-80 amino acids recruits homologous domains of different cytoplasmic proteins including death domain proteins, death effector domain proteins, and caspase recruitment domain proteins, all of which propagate the signal leading to activation of caspase-8. By contrast, TNF receptors lacking the death domain trimerize after ligand binding, thus activating an alternative pathway consisting of TNF receptor-associated factors (TRAFs) with a death domain. In turn, the engagement of TRAFs activates caspase-8. In addition to this proapoptotic role, TNF signalling could also induce a rescue pathway through activation of NF- B to prevent cell death. The balance between these two pathways determines the cell's fate. The evolution of TNF receptor genes exemplifies the derivation of membrane-anchored and soluble truncated proteins that serve as decoy receptors or binding proteins to sequester the ligands. Some TNF family ligands are also membrane-anchored becoming soluble following proteolysis. The P75NPR neurotrophin co-receptor is a member of the TNF receptor family The p75 neurotrophin receptor (p75NPR) is a proapoptotic receptor with a death domain that cooperates with three receptor tyrosine kinases (Trk A, B, and C) with antiapoptotic roles. Although p75NTR binds all neurotrophins with similar affinity, the Trk proteins confer ligand specificity. Trks form homodimers and p75 NPR forms homodimers or homotrimers, resulting in a multimeric heterologous complex. The stoichiometry of these interactions serves to specify downstream cellular effects. Several splicing variants of both p75 NPR and Trks also contribute to the complexity of regulation in this system.
no tree for this subfamily