Structural basis for auxiliary subunit KCTD16 regulation of the GABABreceptor

Author:

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

Abstract

Metabotropic GABABreceptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABABreceptor complexes contain the principal subunits GABAB1and GABAB2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABABreceptors and modify the kinetics of GABABreceptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABABreceptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABAB2receptor. A single GABAB2C-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 GABABreceptors 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 GABABreceptors. Defining the binding interface of GABABreceptor and KCTD reveals a potential regulatory site for modulating GABAB-receptor function in the brain.

Funder

HHS | National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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