Mutations of ovine and bovine placental lactogens change, in different ways, the biological activity mediated through homologous and heterologous lactogenic receptors

The biological activities of ovine (o) and bovine (b) placental lactogens ( PLs) and their mutated analogues were compared using several binding and il l vitro bioassays. In almost all cases, the biological activities of these analogues mediated through rat (r) prolactin receptor (PRLR) showed little or no change, despite a remarkable decrease in their capacity to bind tu th e extracellular domain of rPRLR and despite compromised stability of the 2: 1 complexes. These results indicate that mutations impairing the ability of oPL or bPL to form stable complexes with lactogenic receptors do not neces sarily lead to a decrease in the biological activity, because the transient existence of the homodimeric complex is still sufficient to initiate the s ignal transduction. In contrast, oPL and bPL analogues completely, or almos t completely, lost their ability to activate homologous PRLRs, and some of them even acted as site-2 antagonists. To explain the difference between th e activity transduced through homologous and that transduced through hetero logous PRLRs, we propose the novel term 'minimal time of homodimer persiste nce'. This concept assumes that in order to initiate the signal transduction, the associated kinase JAK2 has to be transphosphorylated and this requires a ' minimal time' of homodimer existence. In the case of homologous interaction between ruminant PLs and homologous PRLRs, this 'minimal time' is met, tho ugh the interaction with homologous PRLRs has a shorter half-line than that with heterologous PRLRs. Therefore oPL or bPL are active in cells possessi ng both homologous and heterologous PRLRs. Mutations of oPL or bPL lead to reduced affinity and, consequently, the 'time of homodimer persistence' is shortened. Although in the case of heterologous interaction the 'minimal ti me' is still sufficient to initiate the biological activity, in homologous interactions, which are already weaker than heterologous interactions, furt her destabilization of the complex shortens its persistence to below the 'm inimal time', leading to full or partial loss of biological activity.