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Helix 8 of leukotriene B₄ type-2 receptor is required for the folding to pass the quality control in the endoplasmic reticulum

Daisuke Yasuda^*, Toshiaki Okuno, Takehiko Yokomizo, Tetsuya Hori, Nobuaki Hirota^*, Tomomi Hashidate^*, Masashi Miyano, Takao Shimizu^* and Motonao Nakamura^*,1

^* Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan;

Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and

Structural Biophysics Laboratory, RIKEN Harima Institute at Spring-8, Hyogo, Japan

¹ Correspondence: Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: moto-nakamura{at}umin.net

Many G protein-coupled receptors (GPCRs) possess a putative cytoplasmic helical domain, termed helix 8 (H8), at the proximal region of the C-terminal tail. However, the significance of this domain is not fully understood. Here, we demonstrate the requirement of H8 for the proper folding of GPCRs for passage through the quality control in the endoplasmic reticulum (ER). In the human leukotriene B₄ type-2 receptor (hBLT2), lack of H8 led to an accumulation of the receptor (hBLT2/H8) in the ER. Similar results were obtained in two representative human GPCRs, dopamine type-1 and lysophosphatidic acid type-2 receptors, which were engineered to lack H8. Treatment with the several ligands, which act as pharmacological chaperones, facilitated the surface expression of hBLT2/H8. The surface-trafficked hBLT2/H8 exhibited an agonist-evoked increase in Ca²⁺, demonstrating that H8 is not critical for ligand binding and activation of coupled G proteins. Thus, these results suggest that the H8 region of hBLT2 plays an important role in transport-competent receptor folding.—Yasuda, D., Okuno, T., Yokomizo, T., Hori, T., Hirota, N., Hashidate, T., Miyano, M., Shimizu, T., Nakamura, M. Helix 8 of leukotriene B₄ type-2 receptor is required for the folding to pass the quality control in the endoplasmic reticulum.

Key Words: G protein-coupled receptor • trafficking • pharmacological chaperone • ERAD • 12-HHT

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