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Heterodimeric coiled-coil interactions of human GABAB receptor

Significance Human GABAB receptor transmits inhibitory signals in the brain. Defects in the receptor are linked to several neurological diseases, including epilepsy and spasticity. The GABAB receptor consists of two subunits, GABAB receptor 1 (GBR1) and GABAB receptor 2 (GBR2). GBR1 is trapped inside the cell because it contains an endoplasmic reticulum retention signal that targets the receptor to the intracellular compartment. This retention signal is masked by coiled-coil interaction between GBR1 and GBR2 when the two subunits associate. The crystal structure of a coiled-coil complex between the GABAB receptor subunits reveals the heterodimeric interaction that is responsible for facilitating the surface transport of the intact receptor. Metabotropic GABAB receptor is a G protein-coupled receptor that mediates inhibitory neurotransmission in the CNS. It functions as an obligatory heterodimer of GABAB receptor 1 (GBR1) and GABAB receptor 2 (GBR2) subunits. The association between GBR1 and GBR2 masks an endoplasmic reticulum (ER) retention signal in the cytoplasmic region of GBR1 and facilitates cell surface expression of both subunits. Here, we present, to our knowledge, the first crystal structure of an intracellular coiled-coil heterodimer of human GABAB receptor. We found that polar interactions buried within the hydrophobic core determine the specificity of heterodimer pairing. Disruption of the hydrophobic coiled-coil interface with single mutations in either subunit impairs surface expression of GBR1, confirming that the coiled-coil interaction is required to inactivate the adjacent ER retention signal of GBR1. The coiled-coil assembly buries an internalization motif of GBR1 at the heterodimer interface. The ER retention signal of GBR1 is not part of the core coiled-coil structure, suggesting that it is sterically shielded by GBR2 upon heterodimer formation.