Structural evidence for visual arrestin priming via complexation of phosphoinositols

• Published in: Structure (London) Vol. 30; no. 2; pp. 263 - 277.e5
• Main Authors: Sander, Christopher L., Luu, Jennings, Kim, Kyumhyuk, Furkert, David, Jang, Kiyoung, Reichenwallner, Joerg, Kang, MinSoung, Lee, Ho-Jun, Eger, Bryan T., Choe, Hui-Woog, Fiedler, Dorothea, Ernst, Oliver P., Kim, Yong Ju, Palczewski, Krzysztof, Kiser, Philip D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 03.02.2022
• Subjects: (1,4,5) myo-D-inositol triphosphate; Animals; arrestin; Arrestin - chemistry; Arrestin - metabolism; Cattle; crystal structure; Crystallography, X-Ray; G protein-coupled receptor; GPCR; Inositol Phosphates - metabolism; InsP3; InsP6; Mice; Models, Molecular; myo-D-inositol hexakisphosphate; phospholipase C; photoreceptor; phototransduction; Protein Conformation; Protein Domains; retina; Rhodopsin - metabolism; Sequence Analysis, RNA; Single-Cell Analysis; vision; G protein-coupled receptor; phospholipase C; (1,4,5) myo-D-inositol triphosphate; photoreceptor; InsP3; arrestin; InsP6; phototransduction; vision; retina; crystal structure; myo-D-inositol hexakisphosphate; GPCR; InsP
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2021.10.002

Visual arrestin (Arr1) terminates rhodopsin signaling by blocking its interaction with transducin. To do this, Arr1 translocates from the inner to the outer segment of photoreceptors upon light stimulation. Mounting evidence indicates that inositol phosphates (InsPs) affect Arr1 activity, but the Arr1-InsP molecular interaction remains poorly defined. We report the structure of bovine Arr1 in a ligand-free state featuring a near-complete model of the previously unresolved C-tail, which plays a crucial role in regulating Arr1 activity. InsPs bind to the N-domain basic patch thus displacing the C-tail, suggesting that they prime Arr1 for interaction with rhodopsin and help direct Arr1 translocation. These structures exhibit intact polar cores, suggesting that C-tail removal by InsP binding is insufficient to activate Arr1. These results show how Arr1 activity can be controlled by endogenous InsPs in molecular detail. [Display omitted] •The regulatory C-tail/N-domain interaction of arrestin-1 is resolved•Arrestin-1 binds InsPs using many of the same residues that hold the C-tail•InsP binding does not activate arrestin-1, but partially removes the C-tail Sander et al. resolve how the C-tail regulatory domain and the N-domain of arrestin 1 interact and maintain correct cellular localization. They further show that InsPs, including InsP3, compete for N-domain contacts responsible for binding the C-tail, thereby priming the structure for translocation.