Structural basis for KCTD-mediated rapid desensitization of GABAB signalling.

The GABAB (?-aminobutyric acid type B) receptor is one of the principal inhibitory neurotransmitter receptors in the brain, and it signals through heterotrimeric G proteins to activate a variety of effectors, including G-protein-coupled inwardly rectifying potassium channels (GIRKs)1,2. GABAB-receptor signalling is tightly regulated by auxiliary subunits called KCTDs, which control the ...
kinetics of GIRK activation and desensitization3-5. However, the mechanistic basis for KCTD modulation of GABAB signalling remains incompletely understood. Here, using a combination of X-ray crystallography, electron microscopy, and functional and biochemical experiments, we reveal the molecular details of KCTD binding to both GABAB receptors and G-protein ?? subunits. KCTDs associate with the receptor by forming an asymmetric pentameric ring around a region of the receptor carboxy-terminal tail, while a second KCTD domain, H1, engages in a symmetric interaction with five copies of G?? in which the G-protein subunits also interact directly with one another. We further show that KCTD binding to G?? is highly cooperative, defining a model in which KCTD proteins cooperatively strip G proteins from GIRK channels to induce rapid desensitization following receptor activation. These results provide a framework for understanding the molecular basis for the precise temporal control of GABAB signalling by KCTD proteins.
Mesh Terms:
Crystallography, X-Ray, G Protein-Coupled Inwardly-Rectifying Potassium Channels, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Humans, Intracellular Signaling Peptides and Proteins, Microscopy, Electron, Models, Biological, Models, Molecular, Nerve Tissue Proteins, Protein Binding, Protein Domains, Proteins, Receptors, GABA-B, Signal Transduction
Nature
Date: Mar. 01, 2019
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