Browsing by Author "Branschädel, Marcus"

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    Analysis of molecular components essential for the formation of signaling competent TNF-TNFR complexes
    (2007) Branschädel, Marcus; Scheurich, Peter ( Prof. Dr.)
    Signaling of Tumor Necrosis Factor Receptors (TNFR) coincides with the formation of microscopically visible aggregates. At least two interactions are required for such cluster formation: One ligand-dependent, and one ligand-independent. The second type of interaction was investigated by using chimeric receptors consisting of TNFR1 or TNFR2 that were fused to the intracellular parts of Fas. These molecules were used as a model system to analyze the role(s) of the extracellular cysteine rich domains (CRDs) as well as the stemand transmembrane regions during signal formation. Whereas CRD2 and -3 directly contact the ligand within a signaling-competent complex, the CRD1 has several roles: It is a scaffold for CRD2, necessary for receptor-receptor interactions without ligand and essential for the formation of signaling competent complexes after ligand binding. In addition, the exchange of the CRD1 between receptors revealed that this domain also contributes to the discrimination of soluble versus membrane-bound ligand. Furthermore, the stem- and transmembrane regions influence the chemical reactivity towards the homo-bifunctional crosslinker BS3. The amount of cross-linkable receptors may be indicative for the strength of a homophilic receptor-receptor interaction that, together with the half-times of the ligand-receptor interaction, determine the generation of an intracellular signal. The experimental data are summarized into a hypothetical model of a ligand-induced hexagonal lattice of ligand-receptor complexes. Such a pattern would allow the efficient activation of intracellularly recruited and enzymatically active proteins (e.g. kinases and caspases) as these are believed to require a dimerization for activation, although ligands of the TNF family display a three-fold symmetry.