Architecture and assembly mechanism of native glycine receptors

Article

关键词: SIZE-EXCLUSION CHROMATOGRAPHY;    CRYOELECTRON MICROSCOPY;    ACETYLCHOLINE-RECEPTOR;    BINDING-PROPERTIES;    CRYO-EM;    SUBUNIT;    STOICHIOMETRY;    IDENTIFICATION;    REGION;   

DOI  :  10.1038/s41586-021-04022-z

来源: SCIE

【 摘 要 】

Glycine receptors (GlyRs) are pentameric, 'Cys-loop' receptors that form chloride-permeable channels and mediate fast inhibitory signalling throughout the central nervous system(1,2). In the spinal cord and brainstem, GlyRs regulate locomotion and cause movement disorders when mutated(2,3). However, the stoichiometry of native GlyRs and the mechanism by which they are assembled remain unclear, despite extensive investigation(4-8). Here we report cryo-electron microscopy structures of native GlyRs from pig spinal cord and brainstem, revealing structural insights into heteromeric receptors and their predominant subunit stoichiometry of 4 alpha:1 beta. Within the heteromeric pentamer, the beta(+)-alpha(-) interface adopts a structure that is distinct from the alpha(+)-alpha(-) and alpha(+)-beta(-) interfaces. Furthermore, the beta-subunit contains a unique phenylalanine residue that resides within the pore and disrupts the canonical picrotoxin site. These results explain why inclusion of the beta-subunit breaks receptor symmetry and alters ion channel pharmacology. We also find incomplete receptor complexes and, by elucidating their structures, reveal the architectures of partially assembled alpha-trimers and alpha-tetramers.

【 授权许可】

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