Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin
Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin
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DOI：
10.1038/ncomms6767
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发表时间：
2014-12-01
影响因子：
16.6
通讯作者：
Schindelin, Hermann
中科院分区：
文献类型：
--
作者：
Maric, Hans Michael;Kasaragod, Vikram Babu;Schindelin, Hermann
γ-氨基丁酸A型和甘氨酸受体(GABA(A)Rs，GlyRs)是主要的抑制性神经递质受体，与许多突触功能、功能障碍和人类疾病有关。GABA(A)Rs是重要的药物靶点，通过与支架蛋白Gen的直接相互作用来调节。在这里，我们通过对Gen-GABA(A)Rα3复合体的化学、生物物理和结构研究，推导出这种相互作用的分子基础，揭示了α3肽的N末端区域与GlyRβ亚基占据相同的结合位置，而在所有突触GABA(A)Rα亚单位中保守的C末端部分进行了独特的相互作用。通过热力学分析，确定了两个残基是决定其亚基偏好性的主要因素。本研究首次从结构上证实了Gen诱导的GABA(A)Rs的突触聚集，为进一步研究抑制性突触强度的调节以及针对Gen-GABA(A)R相互作用的机制和治疗相关化合物的开发提供了一个框架。
gamma-Aminobutyric acid type A and glycine receptors (GABA(A)Rs, GlyRs) are the major inhibitory neurotransmitter receptors and contribute to many synaptic functions, dysfunctions and human diseases. GABA(A)Rs are important drug targets regulated by direct interactions with the scaffolding protein gephyrin. Here we deduce the molecular basis of this interaction by chemical, biophysical and structural studies of the gephyrin-GABA(A)R alpha 3 complex, revealing that the N-terminal region of the alpha 3 peptide occupies the same binding site as the GlyR beta subunit, whereas the C-terminal moiety, which is conserved among all synaptic GABA(A)R alpha subunits, engages in unique interactions. Thermodynamic dissections of the gephyrin-receptor interactions identify two residues as primary determinants for gephyrin's subunit preference. This first structural evidence for the gephyrin-mediated synaptic accumulation of GABA(A)Rs offers a framework for future investigations into the regulation of inhibitory synaptic strength and for the development of mechanistically and therapeutically relevant compounds targeting the gephyrin-GABA(A)R interaction.