Biological Implications of Transient Receptor Dimerization

Functional and structural information suggests that the role of receptor homodimerization is more complicated than simply bringing the cytoplasmic elements of the receptors together. For instance, structural studies of erythropoietin (EPO) and its receptor (EPO-R) indicate that a function of the hormone is to establish a fairly exact receptor alignment, as well as to induce dimerization [33-36]. Based on patterns of cross-hormone and cross-species activities and the known structural differences in the active complexes, exact receptor orientation is probably not as crucial for prolactin and growth hormone systems.

Although strict orientation effects may not be crucial, it appears that the dynamics governing the stability of the aggregated signaling complex are an important regulatory element for the prolactins. Consequently, the inefficient site 2 binding is likely an evolved characteristic of homologous prolactin systems distinguishing their homodimerization process from those of GH and EPO. To explain mutagenesis data influencing site 2 binding, Herman et al. [37] have suggested a minimal-time mechanism based on the assumption that signal transduction requires a minimal persistence lifetime for the homodimer to facilitate effective transphospho-rylation of the associated JAK2 kinases. Once this goal is achieved, the existence of the dimerized receptors is no longer obligatory. It is proposed that this minimal time is generally shorter for PRL-R than for GH-R, perhaps because the JAK2 kinase is preassociated in the case of PRL-R [38] but not GHR [39]. The minimal-time hypothesis is also supported by a study by Pearce et al. [40], who engineered tighter and weaker binding interactions between hGH and hGH-R. They found that increasing affinities of the hGH-hGHR associations at both site 1 and site 2 produced no measurable increases in biological activity. However, reducing affinity at site 1 30-fold marked a point that appeared to correspond to a threshold where activity was affected, suggesting that wildtype hGH-hGH-R affinity is higher at site 1 than it needs to be to sustain full biological activity.

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