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Membrane-embedded mechanosensitive (MS) proteins, including ion channels and G-protein coupled receptors (GPCRs), are essential for the transduction of external mechanical stimuli into biological signals. The angiotensin II type 1 (AT1) receptor plays many important roles in cardiovascular regulation and is associated with diseases such as hypertension and congestive heart failure. The membrane-mediated activation of the AT1 receptor is not well understood, despite this being one of the most widely studied GPCRs within the context of biased agonism. Here, we use extensive molecular dynamics (MD) simulations to characterize the effect of the local membrane environment on the activation of the AT1 receptor. We show that membrane thickness plays an important role in the stability of active and inactive states of the receptor, as well as the dynamic interchange between states. Furthermore, our simulation results show that membrane tension is effective in driving large-scale structural changes in the inactive state such as the outward movement of transmembrane helix 6 to stabilize intermediate active-like conformations. We conclude by comparing our simulation observations with AlphaFold 2 predictions, as a proxy to experimental structures, to provide a framework for how membrane mediated stimuli can facilitate activation of the AT1 receptor through the β-arrestin signaling pathway.
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Membrane mediated mechanical stimuli produces distinct active-like states in the AT1 receptor
Abstract The Angiotensin II Type 1 (AT1) receptor is one of the most widely studied GPCRs within the context of biased signaling. While the AT1 receptor is activated by agonists such as the peptide AngII, it can also be activated by mechanical stimuli such as membrane stretch or shear in the absence of a ligand. Despite the importance of mechanical activation of the AT1 receptor in biological processes such as vasoconstriction, little is known about the structural changes induced by external physical stimuli mediated by the surrounding lipid membrane. Here, we present a systematic simulation study that characterizes the activation of the AT1 receptor under various membrane environments and mechanical stimuli. We show that stability of the active state is highly sensitive to membrane thickness and tension. Structural comparison of membrane-mediated vs. agonist-induced activation shows that the AT1 receptor has distinct active conformations. This is supported by multi-microsecond free energy calculations that show unique landscapes for the inactive and various active states. Our modeling results provide structural insights into the mechanical activation of the AT1 receptor and how it may produce different functional outcomes within the framework of biased agonism.
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- PAR ID:
- 10438762
- Publisher / Repository:
- Nature Publishing Group
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 14
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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