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Structure of beta-arrestin1 in complex with D6Rpp
Structural highlights
FunctionACKR2_HUMAN Atypical chemokine receptor that controls chemokine levels and localization via high-affinity chemokine binding that is uncoupled from classic ligand-driven signal transduction cascades, resulting instead in chemokine sequestration, degradation, or transcytosis. Also known as interceptor (internalizing receptor) or chemokine-scavenging receptor or chemokine decoy receptor. Acts as a receptor for chemokines including CCL2, CCL3, CCL3L1, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL17, CCL22, CCL23, CCL24, SCYA2/MCP-1, SCY3/MIP-1-alpha, SCYA5/RANTES and SCYA7/MCP-3. Upon active ligand stimulation, activates a beta-arrestin 1 (ARRB1)-dependent, G protein-independent signaling pathway that results in the phosphorylation of the actin-binding protein cofilin (CFL1) through a RAC1-PAK1-LIMK1 signaling pathway. Activation of this pathway results in up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. By scavenging chemokines in tissues, on the surfaces of lymphatic vessels, and in placenta, plays an essential role in the resolution (termination) of the inflammatory response and in the regulation of adaptive immune responses. Plays a major role in the immune silencing of macrophages during the resolution of inflammation. Acts as a regulator of inflammatory leukocyte interactions with lymphatic endothelial cells (LECs) and is required for immature/mature dendritic cells discrimination by LECs.[1] [2] Publication Abstract from PubMedbeta-arrestins (betaarrs) are multifunctional proteins involved in signaling and regulation of seven transmembrane receptors (7TMRs), and their interaction is driven primarily by agonist-induced receptor activation and phosphorylation. Here, we present seven cryo-electron microscopy structures of betaarrs either in the basal state, activated by the muscarinic receptor subtype 2 (M2R) through its third intracellular loop, or activated by the betaarr-biased decoy D6 receptor (D6R). Combined with biochemical, cellular, and biophysical experiments, these structural snapshots allow the visualization of atypical engagement of betaarrs with 7TMRs and also reveal a structural transition in the carboxyl terminus of betaarr2 from a beta strand to an alpha helix upon activation by D6R. Our study provides previously unanticipated molecular insights into the structural and functional diversity encoded in 7TMR-betaarr complexes with direct implications for exploring novel therapeutic avenues. Molecular insights into atypical modes of beta-arrestin interaction with seven transmembrane receptors.,Maharana J, Sano FK, Sarma P, Yadav MK, Duan L, Stepniewski TM, Chaturvedi M, Ranjan A, Singh V, Saha S, Mahajan G, Chami M, Shihoya W, Selent J, Chung KY, Banerjee R, Nureki O, Shukla AK Science. 2024 Jan 5;383(6678):101-108. doi: 10.1126/science.adj3347. Epub 2024 , Jan 4. PMID:38175886[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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