Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor

Hao Zuo, Ian Glaaser, Yulin Zhao, Igor Kurinov, Lidia Mosyak, Haonan Wang, Jonathan Liu, Jinseo Park, Aurel Frangaj, Emmanuel Sturchler, Ming Zhou, Patricia McDonald, Yong Geng, Paul A. Slesinger, Qing R. Fan

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Metabotropic GABAB receptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABAB receptor complexes contain the principal subunits GABAB1 and GABAB2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABAB receptors and modify the kinetics of GABAB receptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABAB receptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABAB2 receptor. A single GABAB2 C-terminal peptide is bound to the interior of an open pentamer formed by the oligomerization domain of five KCTD16 subunits. Mutation of specific amino acids identified in the structure of the GABAB2–KCTD16 interface disrupted both the biochemical association and functional modulation of GABAB receptors and G protein-activated inwardly rectifying K+ channel (GIRK) channels. These interfacial residues are conserved among KCTDs, suggesting a common mode of KCTD interaction with GABAB receptors. Defining the binding interface of GABAB receptor and KCTD reveals a potential regulatory site for modulating GABAB-receptor function in the brain.

Original languageEnglish
Pages (from-to)8370-8379
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number17
StatePublished - 2019


  • Crystal structure
  • GABA receptor
  • KCTD
  • Principal and auxiliary subunits


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