Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.
Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.
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DOI：
10.1016/j.celrep.2014.09.029
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发表时间：
2014-10-23
期刊：
影响因子：
8.8
通讯作者：
Greger IH
中科院分区：
文献类型：
--
作者：
Cais O;Herguedas B;Krol K;Cull-Candy SG;Farrant M;Greger IH
AMPA型谷氨酸受体（AMPAR）介导兴奋性突触的快速神经传递。AMPAR激活触发的突触后去极化的程度和保真度由AMPAR辅助亚基（包括跨膜AMPAR调节蛋白（TARPs））决定。TARP深刻地影响门控，这种效应被认为是通过与AMPAR离子通道和配体结合结构域（LBD）的相互作用介导的。在这里，我们表明，远端N-末端结构域（NTD）有助于TARP调制。NTD-LBD接头的改变导致AMPAR门控中的TARP依赖性和TARP选择性变化。使用肽阵列，我们确定了一个TARP相互作用区域的NTD和定义的路径TARP接触沿着LBD表面。此外，我们映射TARP本身的关键结合位点，并表明这些残基的突变介导门控调制。我们的数据揭示了一个TARP依赖的变构作用的AMPAR NTD，并建议TARP绑定触发了激烈的重组的AMPAR复合物。NTD接头对AMPAR门控具有TARP依赖性和TARP特异性影响肽阵列揭示了TARP与AMPAR的两个胞外结构域的结合TARP结合触发了AMPAR的结构重组突触AMPA型谷氨酸受体（AMPAR）的门控特性由跨膜AMPAR调节蛋白（TARP）调节，但关于它们在分子水平上的结合的知识有限。在这里，Cais et al.映射这两个伙伴分子的相互作用，并揭示了受体N-末端结构域的功能作用。
AMPA-type glutamate receptors (AMPARs) mediate fast neurotransmission at excitatory synapses. The extent and fidelity of postsynaptic depolarization triggered by AMPAR activation are shaped by AMPAR auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). TARPs profoundly influence gating, an effect thought to be mediated by an interaction with the AMPAR ion channel and ligand binding domain (LBD). Here, we show that the distal N-terminal domain (NTD) contributes to TARP modulation. Alterations in the NTD-LBD linker result in TARP-dependent and TARP-selective changes in AMPAR gating. Using peptide arrays, we identify a TARP interaction region on the NTD and define the path of TARP contacts along the LBD surface. Moreover, we map key binding sites on the TARP itself and show that mutation of these residues mediates gating modulation. Our data reveal a TARP-dependent allosteric role for the AMPAR NTD and suggest that TARP binding triggers a drastic reorganization of the AMPAR complex. The NTD linker has a TARP-dependent and TARP-specific impact on AMPAR gating Peptide arrays reveal binding of TARPs to both extracellular domains of AMPARs A structural reorganization of AMPARs is triggered by TARP binding Gating properties of synaptic AMPA-type glutamate receptors (AMPARs) are modulated by the transmembrane AMPAR regulatory proteins (TARPs), yet knowledge about their binding on a molecular level is limited. Here, Cais et al. map this interaction on both partner molecules and reveal a functional role for the receptor N-terminal domain.
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影响因子：
64.8
作者：
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通讯作者：
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