Structural basis for KCTD-mediated rapid desensitization of GABA_B signalling

Journal Article · 26 February 2019 · Nature (London)

DOI: https://doi.org/10.1038/S41586-019-0990-0 · OSTI ID:1604178

Zheng, Sanduo ^[1]; Abreu, Nohely ^[2]; Levitz, Joshua ^[2]; Kruse, Andrew C. ^[1]

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1. Harvard Medical School, Boston, MA (United States)
2. Cornell Univ., Ithaca, NY (United States). Weill Medical College

The GABA_B (γ-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). GABA_B-receptor signalling is tightly regulated by auxiliary subunits called KCTDs, which control the kinetics of GIRK activation and desensitization. However, the mechanistic basis for KCTD modulation of GABA_B 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 GABA_B receptors and G-protein βγ 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 Gβγ in which the G-protein subunits also interact directly with one another. We further show that KCTD binding to Gβγ 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 GABA_B signalling by KCTD proteins.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: National Science Foundation (NSF); USDOE
• OSTI ID: 1604178
• Journal Information: Nature (London), Journal Name: Nature (London) Journal Issue: 7746 Vol. 567; ISSN 0028-0836
• Publisher: Nature Publishing GroupCopyright Statement
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES