Patel Nishaben M, Ripoll Léa, Peach Chloe J, Ma Ning, Blythe Emily E, Vaidehi Nagarajan, Bunnett Nigel W, von Zastrow Mark, Sivaramakrishnan Sivaraj
Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN, USA.
Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
Nat Commun. 2024 Dec 6;15(1):10636. doi: 10.1038/s41467-024-55053-9.
G protein-coupled receptor (GPCR) endocytosis is canonically associated with β-arrestins. Here, we delineate a β-arrestin-independent endocytic pathway driven by the cytoskeletal motor, myosin VI. Myosin VI engages GIPC, an adaptor protein that binds a PDZ sequence motif present at the C-terminus of several GPCRs. Using the D2 dopamine receptor (D2R) as a prototype, we find that myosin VI regulates receptor endocytosis, spatiotemporal localization, and signaling. We find that access to the D2R C-tail for myosin VI-driven internalization is controlled by an interaction between the C-tail and the third intracellular loop of the receptor. Agonist efficacy, co-factors, and GIPC expression modulate this interaction to tune agonist trafficking. Myosin VI is differentially regulated by distinct GPCR C-tails, suggesting a mechanism to shape spatiotemporal signaling profiles in different ligand and physiological contexts. Our biophysical and structural insights may advance orthogonal therapeutic strategies for targeting GPCRs through cytoskeletal motor proteins.
G蛋白偶联受体（GPCR）的内吞作用通常与β-抑制蛋白相关。在此，我们描述了一种由细胞骨架马达蛋白肌球蛋白VI驱动的不依赖β-抑制蛋白的内吞途径。肌球蛋白VI与GIPC相互作用，GIPC是一种衔接蛋白，可结合存在于几种GPCR C末端的PDZ序列基序。以D2多巴胺受体（D2R）为原型，我们发现肌球蛋白VI调节受体的内吞作用、时空定位和信号传导。我们发现，肌球蛋白VI驱动内化作用对D2R C末端的作用途径是由受体的C末端与第三细胞内环之间的相互作用控制的。激动剂效力、辅助因子和GIPC表达调节这种相互作用以调节激动剂的转运。肌球蛋白VI受不同GPCR C末端的差异调节，这表明在不同配体和生理环境中塑造时空信号图谱的一种机制。我们的生物物理和结构见解可能会推动通过细胞骨架马达蛋白靶向GPCR的正交治疗策略的发展。
