Gephyrin-mediated formation of inhibitory postsynaptic density sheet via phase separation  

作　　者：Guanhua Bai Yu Wang Mingjie Zhang 

机构地区：[1]Division of Life Science,State Key Laboratory of Molecular Neuroscience,Hong Kong University of Science and Technology,Clear Water Bay,Kowloon,Hong Kong,China [2]Center of Systems Biology and Human Health,Hong Kong University of Science and Technology,Clear Water Bay,Kowloon,Hong Kong,China

出　　处：《Cell Research》2021年第3期312-325,共14页细胞研究（英文版）

基　　金：This work was supported by a grant from the Minister of Science and Technology of China(2019YFA0508402);a grant from Human Frontier Science Program(RGP0020/2019);grants from Research Grant Council of Hong Kong(A〇E-M09-12 and C6004-17G)to M.Z.M.Z.is a Kerry Holdings Professor of Science,a Croucher Foundation Senior Fellow,and a Senior Fellow of IAS at HKUST.

摘　　要：Inhibitory synapses are also known as symmetric synapses due to their lack of prominent postsynaptic densities(PSDs)under a conventional electron microscope(EM).Recent cryo-EM tomography studies indicated that inhibitory synapses also contain PSDs,albeit with a rather thin sheet-like structure.It is not known how such inhibitory PSD(iPSD)sheet might form.Here,we demonstrate that the key inhibitory synapse scaffold protein gephyrin,when in complex with either glycine or GABAA receptors,spontaneously forms highly condensed molecular assemblies via phase separation both in solution and on supported membrane bilayers.Multivalent and specific interactions between the dimeric E-domain of gephyrin and the glycine/GABAA receptor multimer are essential for the iPSD condensate formation.Gephyrin alone does not form condensates.The linker between the G-and E-domains of gephyrin inhibits the iPSD condensate formation via autoinhibition.Phosphorylation of specific residues in the linker or binding of target proteins such as dynein light chain to the linker domain regulates gephyrin-mediated glycine/GABAA receptor clustering.Thus,analogous to excitatory PSDs,iPSDs are also formed by phase separation-mediated condensation of scaffold protein/neurotransmitter receptor complexes.

关 键 词：structure. SEPARATION phase 

分 类 号：R741[医药卫生—神经病学与精神病学]