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bioRxiv · 10.1101/2023.03.06.531433

Distinct activation mechanisms of β-arrestin 1 revealed by 19F NMR spectroscopy

Zhai, R.·Wang, Z.·Chai, Z.·Li, C.·Jin, C.·Hu, Y.
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Abstract

{beta}-Arrestins ({beta}arrs) are functionally versatile proteins that play critical roles in the G-protein-coupled receptor (GPCR) signaling pathways. While the classical theory of GPCR-mediated {beta}arr activation centers around the formation of a stable complex between {beta}arr and the phosphorylated receptor tail, emerging evidences highlight the indispensable contribution from membrane lipids for many receptors. Due to the intrinsic complexity of {beta}arr conformational dynamics, detailed molecular mechanisms of its activation by different binding partners remain elusive. Herein we present a comprehensive study of the structural changes of {beta}arr1 in critical structural regions during activation using 19F NMR method. We demonstrate that phosphopeptides derived from different classes of GPCRs show distinct abilities in inducing {beta}arr1 activation. We further show that the membrane phosphoinositide PIP2 independently modulates {beta}arr1 conformational dynamics without displacing its autoinhibitory carboxyl tail, leading to a distinct partially activated state. Our results delineate two activation mechanisms of {beta}arr1 by different binding partners, uncovering a highly multifaceted conformational energy landscape for this protein family.

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Zhai, R., Wang, Z., Chai, Z., Li, C., Jin, C., Hu, Y.. 2023-03-07. Distinct activation mechanisms of β-arrestin 1 revealed by 19F NMR spectroscopy. https://doi.org/10.1101/2023.03.06.531433

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