Structural basis for KCTD-mediated rapid desensitization of GABAB signalling

Nature
Sanduo ZhengAndrew C Kruse

Abstract

The GABAB (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)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 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 follow...Continue Reading

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Citations

May 8, 2020·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Hiroko Kotajima-Murakami, Kazutaka Ikeda
Apr 30, 2019·Basic & Clinical Pharmacology & Toxicology·Thorsten Fritzius, Bernhard Bettler
Jul 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Linn Samira Mari EvensethIngebrigt Sylte
Dec 29, 2019·Scientific Reports·Giovanni SmaldoneMarco Salvatore
Jun 15, 2019·CNS Neuroscience & Therapeutics·Xinchen TengJ Marie Hardwick
Oct 30, 2020·International Journal of Molecular Sciences·Jordan BlondelleStephan Lange
Nov 13, 2020·Nature Reviews. Drug Discovery·Mette Ishøy RosenbaumKristian Strømgaard
Apr 3, 2021·Neuropharmacology·Alessandra PorcuM Paola Castelli
Oct 16, 2020·Journal of Molecular Biology·Yoojoong KimYunje Cho
Mar 12, 2021·Journal of Virology·Jiahao MaSanduo Zheng
May 19, 2021·Cell Communication and Signaling : CCS·Annapaola AngrisaniMarta Moretti
May 30, 2021·Science Advances·Hamidreza ShayeVadim Cherezov
Dec 23, 2021·Proceedings of the National Academy of Sciences of the United States of America·Brian S MunteanKirill A Martemyanov

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Methods Mentioned

BETA
pull-down
electron-microscopy
size-exclusion
size-exclusion chromatography
affinity purification
transfection

Software Mentioned

Prism GraphPad
Relion
Phenix
Clampfit
Phaser
cisTEM
Fiji
Origin
ImageJ
Coot

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