Biotechnology and Biological Sciences Research Council (BBSRC)
BB/N002113/1
英国
Spanish Ministry of Science, Innovation, and Universities
PID2019-106284GA-I00
英国
引用
ジャーナル: Nat Commun / 年: 2022 タイトル: Mechanisms underlying TARP modulation of the GluA1/2-γ8 AMPA receptor. 著者: Beatriz Herguedas / Bianka K Kohegyi / Jan-Niklas Dohrke / Jake F Watson / Danyang Zhang / Hinze Ho / Saher A Shaikh / Remigijus Lape / James M Krieger / Ingo H Greger / 要旨: AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel ...AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop ('β1'), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance.
超分子 #1: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP ...
超分子
名称: Complex between GluA1/2 AMPA receptor and auxiliary subunit TARP gamma8 タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: #1-#3 / 詳細: GluA2 and TARP8 are expressed as a tandem construct
First, rigid body fit was performed in Chimera using the coordinates of the TMD of 6QKC and the coordinates of the LBD in PDB code 3TKD. Manual model building was performed with Coot and Refinement was performed with Refmac. The TMD and LBD maps obtained independently aided model building but were not used for refinement.
精密化
空間: REAL / プロトコル: RIGID BODY FIT
得られたモデル
PDB-7qhh: Desensitized state of GluA1/2 AMPA receptor in complex with TARP-gamma 8 (TMD-LBD)