Structural basis for auxiliary subunit KCTD16 regulation of the GABA_B receptor.

Abstract

Metabotropic GABA_B receptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABA_B receptor complexes contain the principal subunits GABA_B1 and GABA_B2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABA_B receptors and modify the kinetics of GABA_B receptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABA_B receptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABA_B2 receptor. A single GABA_B2 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 GABA_B2-KCTD16 interface disrupted both the biochemical association and functional modulation of GABA_B 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 GABA_B receptors. Defining the binding interface of GABA_B receptor and KCTD reveals a potential regulatory site for modulating GABA_B-receptor function in the brain.