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Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies

Title
Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies
Authors
Kim, SeungjoonKang, MooseokPark, DongseokLee, Ae-ReeBetz, HeinrichKo, JaewonChang, IksooUm, Ji Won
DGIST Authors
Kim, Seungjoon; Kang, Mooseok; Park, Dongseok; Lee, Ae-Ree; Betz, Heinrich; Ko, JaewonChang, IksooUm, Ji Won
Issue Date
2021-02
Citation
iScience, 24(2), 102037
Type
Article
Author Keywords
Molecular BiologyNeuroscienceStructural Biology
Keywords
MOLECULAR-DYNAMICSPROTEIN GEPHYRININHIBITORY SYNAPSESAUTISMRECEPTORSVARIANTDOMAINAMBER
ISSN
2589-0042
Abstract
Gephyrin is critical for the structure, function, and plasticity of inhibitory synapses. Gephyrin mutations have been linked to various neurological disorders; however, systematic analyses of the functional consequences of these mutations are lacking. Here, we performed molecular dynamics simulations of gephyrin to predict how six reported point mutations might change the structural stability and/or function of gephyrin. Additional in silico analyses revealed that the A91T and G375D mutations reduce the binding free energy of gephyrin oligomer formation. Gephyrin A91T and G375D displayed altered clustering patterns in COS-7 cells and nullified the inhibitory synapse-promoting effect of gephyrin in cultured neurons. However, only the G375D mutation reduced gephyrin interaction with GABAA receptors and neuroligin-2 in mouse brain; it also failed to normalize deficits in GABAergic synapse maintenance and neuronal hyperactivity observed in hippocampal dentate gyrus-specific gephyrin-deficient mice. Our results provide insights into biochemical, cell-biological, and network-activity effects of the pathogenic G375D mutation. © 2021 The Author(s)
URI
http://hdl.handle.net/20.500.11750/13484
DOI
10.1016/j.isci.2021.102037
Publisher
Cell Press
Related Researcher
  • Author Chang, Iksoo Theoretical and Computational Biophysics Laboratory
  • Research Interests Theoretical and Computational Biophysics; Supercomputing Simulation of Biomolecules; 이론?계산 생물물리학; 통계물리학; 단백질체의 슈퍼컴퓨터 모델링 및 시물레이션
Files:
Collection:
Department of Brain SciencesLaboratory of Synapse Formation and Function1. Journal Articles
Department of Brain SciencesTheoretical and Computational Biophysics Laboratory1. Journal Articles
Department of Brain SciencesSynapse Disorder Laboratory1. Journal Articles


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