9h9e
Cryo-EM structure of the human GABAA receptor alpha1 subunit in complex with the assembly factor NACHO/TMEM35A
Structural highlights
DiseaseGBRA1_HUMAN Juvenile myoclonic epilepsy;Childhood absence epilepsy;Dravet syndrome. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionGBRA1_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel (By similarity). Publication Abstract from PubMedPentameric ligand-gated ion channels (pLGICs) are cell surface receptors of crucial importance for animal physiology(1-4). This diverse protein family mediates the ionotropic signals triggered by major neurotransmitters and includes gamma-aminobutyric acid receptors (GABA(A)Rs) and acetylcholine receptors (nAChRs). Receptor function is fine-tuned by a myriad of endogenous and pharmacological modulators(3). A functional pLGIC is built from five homologous, sometimes identical, subunits, each containing a beta-scaffold extracellular domain (ECD), a four-helix transmembrane domain (TMD) and intracellular loops of variable length. Although considerable progress has been made in understanding pLGICs in structural and functional terms, the molecular mechanisms that enable their assembly at the endoplasmic reticulum (ER)(5) in a vast range of potential subunit configurations(6) remain unknown. Here, we identified candidate pLGICs assembly factors selectively associated with an unassembled GABA(A)R subunit. Focusing on one of the candidates, we determined the cryo-EM structure of an assembly intermediate containing two alpha1 subunits of GABA(A)R each bound to an ER-resident membrane protein NACHO. The structure showed how NACHO shields the principal (+) transmembrane interface of alpha1 subunits containing an immature extracellular conformation. Crosslinking and structure-prediction revealed an adjacent surface on NACHO for beta2 subunit interactions to guide stepwise oligimerisation. Mutations of either subunit-interacting surface on NACHO also impaired the formation of homopentameric alpha7 nAChRs, pointing to a generic framework for pLGIC assembly. Our work provides the foundation for understanding the regulatory principles underlying pLGIC structural diversity. Mechanism of NACHO-mediated assembly of pentameric ligand-gated ion channels.,Hooda Y, Sente A, Judy RM, Smalinskaite L, Peak-Chew SY, Naydenova K, Malinauskas T, Hardwick SW, Chirgadze DY, Aricescu AR, Hegde RS bioRxiv [Preprint]. 2024 Nov 15:2024.10.28.620708. doi: , 10.1101/2024.10.28.620708. PMID:39553992[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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