Cofactoring and Dimerization of Proteinase-Activated Receptors

Activated protein C: biased for translation

“…Thus, other PAR3-effector interactions are required for signal induction, diversification, and regulation ( Figure 3). PAR-effector complexes are hypothesized to involve the formation of PAR-PAR heterodimers and homodimers, 43 which may enable PARinduced transactivation of other PARs, integrate the transactivation of other GPCRs such as S1P1, 18,25,26 and incorporate cooperative cross talk with integrins such as Mac1 44,45 or other receptors such as ApoER2 46,47 or Tie2. 20,42,48 Formation of these complexes may achieve a signaling bias by promoting or discouraging the association of particular G-protein ensembles, 49,50 by recruiting b-arrestins, 30 or by incorporating nontraditional PAR signaling pathways via transactivations such as the activation of Tie2 by noncanonical activation of PAR3.…”

PARtitioning protease signaling

“…

and spacer domains sequentially to the metalloprotease domain progressively increases its proteolytic activity, 8 suggesting that each of these amino-terminal domains is critical for substrate recognition. Binding experiments have demonstrated that each individual amino-terminal domain (except the metalloprotease domain) appears to bind VWF73 with appreciable affinities (K D , ;100-500 mM), but the MDTCS domains together bind VWF73 with much higher affinity (K D , ;7 nM).

…”

“…5,7 These data suggest that parmodulins are primarily blocking Ga q pathways; this needs to be formally tested. Endogenous regulation of PAR1 activation and signaling in endothelial cells is regulated by heterodimerization, 8 cofactors, subcellular localization, 9,10 and alternative cleavage sites, all of which have the potential to be differentially affected by orthosteric inhibitors and parmodulins. Like many GPCRs, PAR1 can heterodimerize with multiple partners, and each of these interactions can influence the cellular consequences of receptor activation.…”

“…Following PAR1 activation by thrombin, PAR1 is able transactivate PAR2. 8 Because vorapaxar is directed to the ligand-binding site of PAR1, one would expect that it would not influence PAR2 transactivation. In contrast, parmodulins may influence PAR1-PAR2 interactions either directly, by disrupting heterodimers, or indirectly, through PAR1 allostery.…”

“…Binding experiments have demonstrated that each individual amino-terminal domain (except the metalloprotease domain) appears to bind VWF73 with appreciable affinities (K D , ;100-500 mM), but the MDTCS domains together bind VWF73 with much higher affinity (K D , ;7 nM). 8 Furthermore, a large 8 or small 9 deletion or even a point mutation 9,10 in any of these noncatalytic domains results in significant impairment of ADAMTS13 activity. Together, these findings suggest that the MDTCS domains work in concert for substrate recognition and proteolysis.…”