Receptor-effector complex interactions

Binding of the ligand of the Fas receptor triggers clustering of the receptor and association of the cofactor FADD (fas-assodated protein with death domain) which interacts with the receptor via its death domain (DD). Procaspase 8 binds to FADD via a common DED (death effector domain) motif and is thereby also recruited into the Fas-receptor associated complex. Due to the clustering of the proteins, proximity-induced cleavage of procaspase 8 to the mature initiator caspase 8 takes place. This activates the effector caspases and triggers cell death. 

While the current structural and functional studies have shed lights on the molecular mechanisms of post-receptor signal transduction by the TNFR superfamUy, many important questions remain. One such question is the structural basis for the formation of death receptor signaling complexes, involving DD-DD and DED-DED interactions. Another question is the molecular basis of TRAP downstream signaling. Does it involve oligomerization and proximity induced activation of down-stream effectors, or conformational modulations Because of the importance of the TNFR superfamily in human disease, an ultimate question lies on the translation of structural and functional studies into therapeutic applications. 

The versatile trimeric G proteins enable different receptor-hormone complexes to modulate the activity of the same effector protein. In the liver, for Instance, glucagon and epinephrine bind to different receptors, but both receptors Interact with and activate the same Gj, which activates adenylyl cyclase, thereby triggering the same metabolic responses. Activation of adenylyl cyclase, and thus the cAMP level. Is proportional to the total concentration of Gsc GTP resulting from binding of both hormones to their respective receptors. 

Considerable evidence suggests that 7TM receptors can exist in two different coexisting conformational states an inactive state R and an active state R. The relative proportion of R and R will depend on both the actual receptor-effector system and the presence of ligands (L) having affinity for the receptor, i.e. able to form complexes with R (LR) and R (LR ). Only R and AR can couple with G-proteins to induce a cellular response (e.g. increase in cAMP levels). If, to simplify, the reversible interaction between the receptor and the G-protein is omitted, the minimal scheme depicting the relationship between A, R, R, LR and LR can be written as follows where ... 

Fig. 4.4 Activation of G-proteins. G-proteins include three subunits (a, p, 7). Interaction of the a-subunit to an agonist stimulated receptor (l-ll) causes the exchange of the bound GDP with GTP (ll-lll). The a-GTP complex and the dimer p-7 dissociated. The a-GTP complex interacted with an effector (El) and the dimer p-7 with another effector (E2) (IV). The a-subunit catalyses hydrolysis of the bound GTP to GDP (V) and reassociated with the dimer p-7 (I). This deactivation of signalling can be accelerated by proteins termed regulators of G-protein signalling (RGS) which have been shown to directly bind to the a-subunit of G-proteins. (Adapted from Gies, J. -P. (1993) Bases de Pharmacologie Moleculaire, Published by Ellipses-Edition Marketing, Paris).

The effect of a biologically active compound is based on its ability to form a complex with a receptor. The intensity of the biological effect is proportional to the stability of this complex, which is dependent on the strength of the interaction of the effector molecule with the active centre of the receptor. The electron structure of the molecule can be decisive for this interaction and this may explain the correlation of ionization potentials and pharmacological properties of certain compounds. 

The action of a hormone is defined as the primary effect on a cell, usually the binding of the hormone to a specific receptor and the resultant interaction between the hormone-receptor complex and an effector system within the cell. The effect of a hormone is an experimental observation that is made either in vitro or in vivo it can be molecular, biochemical or physiological but, when a sufficient number of effects are established, a relationship between the action and effects can be drawn. This can best be described as a pyramid (Figure 12.2). The. function of a hormone is an... 

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