Toward Understanding the Impact of Dimerization Interfaces in Angiotensin II Type 1 Receptor

Abstract

Angiotensin II type 1 receptor (AT1R) is a prototypical class A G protein-coupled receptor (GPCR) that has an important role in cardiovascular pathologies and blood pressure regulation as well as in the central nervous system. GPCRs may exist and function as monomers; however, they can assemble to form higher order structures, and as a result of oligomerization, their function and signaling profiles can be altered. In the case of AT1R, the classical G alpha(q/11) pathway is initiated with endogenous agonist angiotensin II binding. A variety of cardiovascular pathologies such as heart failure, diabetic nephropathy, atherosclerosis, and hypertension are associated with this pathway. Recent findings reveal that AT1R can form homodimers and activate the noncanonical (beta-arrestin-mediated) pathway. Nevertheless, the exact dimerization interface and atomic details of AT1R homodimerization have not been still elucidated. Here, six different symmetrical dimer interfaces of AT1R are considered, and homodimers were constructed using other published GPCR crystal dimer interfaces as template structures. These AT1R homodimers were then inserted into the model membrane bilayers and subjected to all-atom molecular dynamics simulations. Our simulation results along with the principal component analysis and water pathway analysis suggest four different interfaces as the most plausible: symmetrical transmembrane (TM)1,2,8; TM5; TM4; and TM4,5 AT1R dimer interfaces that consist of one inactive and one active protomer. Moreover, we identified ILE238(6.33) as a hub residue in the stabilization of the inactive state of AT1R.