Article
- The EMBO Journal (2007) 26, 2192 - 2205
- doi:10.1038/sj.emboj.7601651
Published online: 29 March 2007
Subject Categories:
Crystal structures of autoinhibitory PDZ domain of Tamalin: implications for metabotropic glutamate receptor trafficking regulation
Takuma Sugi1,4, Takuji Oyama2,4, Takanori Muto1,5, Shigetada Nakanishi3, Kosuke Morikawa2,4 and Hisato Jingami1,6
- Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), Suita, Osaka, Japan
- Department of Structural Biology, Biomolecular Engineering Research Institute (BERI), Suita, Osaka, Japan
- Department of Systems Biology, Osaka Bioscience Institute, Osaka, Japan
- Present address: Institute for Protein Research, Open Laboratories of Advanced Bioscience and Biotechnology (OLABB), Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan
- Present address: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan
- Present address: Office of Graduate Courses for Integrated Research Training, Kyoto University Faculty of Medicine, Yoshida, Sakyo-Ku, Kyoto 606-8501, Japan
Correspondence to:
Hisato Jingami, Office of Graduate Courses for Integrated Research Training, Kyoto University, Yoshida-Konoe, Sakyo-Ku, Kyoto 606-8501, Japan. Tel.: +81 75 753 9493; Fax: +81 75 753 9495. E-mail: jingami@mfour.med.kyoto-u.ac.jp
Kosuke Morikawa, Institute for Protein Research, Open Laboratories of Advanced Bioscience and Biotechnology (OLABB), Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Tel.: +81 6 6872 8201; Fax: +81 6 6872 19. E-mail: morikako@protein.osaka-u.ac.jp
Received 6 October 2006; Accepted 23 February 2007
Abstract
Metabotropic glutamate receptors (mGluRs) function as neuronal G-protein-coupled receptors and this requires efficient membrane targeting through associations with cytoplasmic proteins. However, the molecular mechanism regulating mGluR cell-surface trafficking remains unknown. We report here that mGluR trafficking is controlled by the autoregulatory assembly of a scaffold protein Tamalin. In the absence of mGluR, Tamalin self-assembles into autoinhibited conformations, through its PDZ domain and C-terminal intrinsic ligand motif. X-ray crystallographic analyses visualized integral parts of the oligomeric self-assemblies of Tamalin, which require not only the novel hydrophobic dimerization interface but also canonical and noncanonical PDZ/ligand autoinhibitory interactions. The mGluR cytoplasmic region can competitively bind to Tamalin at a higher concentration, disrupting weak inhibitory interactions. The atomic view of mGluR association suggests that this rearrangement is dominated by electrostatic attraction and repulsion. We also observed in mammalian cells that the association liberates the intrinsic ligand toward a motor protein receptor, thereby facilitating mGluR cell-surface trafficking. Our study suggests a novel regulatory mechanism of the PDZ domain, by which Tamalin switches between the trafficking-inhibited and -active forms depending on mGluR association.
Keywords:
- autoinhibited assembly,
- metabotropic glutamate receptor,
- PDZ domain,
- Tamalin,
- trafficking
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