| This work elucidates the fundamental rules for dimerization and trimerization in alpha helices of transmembrane proteins. There are two major groups of proteins that provide natural testing cases for the rules of dimerization and trimerization of alpha helical transmembrane domains: the dimeric single pass transmembrane receptors (namely cytokine receptors and receptor tyrosine kinases) and the trimeric Class 1 fusion proteins from enveloped viruses. The most important results in this work focus on the dimeric thrombopoietin receptor (TPOr). The related receptor erythropoietin receptor (EPOr) and the STK/RON receptor are also studied.;The TPOr studies have led to a new proposal for receptor signaling. We replace the standard model of ligand induced dimerization and subsequent signaling, with a model involving a preformed but inactive receptor dinner that undergoes ligand induced rotation to become signaling active. We find that this inactive to active rotational transition can be influenced by small molecule receptor agonists that act on the transmembrane domain of TPOr.;The trimerization studies on gp41 from HIV have elucidated a new motif for association, the GGxxG trimer motif Unlike the GxxxG motif in GpA, the association is weak, not strong. This weak trimerization appears to be critical biologically. |
