Stargazin promotes closure of the AMPA receptor ligand-binding domain.
Stargazin promotes closure of the AMPA receptor ligand-binding domain.
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DOI：
10.1085/jgp.201411287
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发表时间：
2014-12
期刊：
影响因子：
--
通讯作者：
Jayaraman V
中科院分区：
文献类型：
--
作者：
MacLean DM;Ramaswamy SS;Du M;Howe JR;Jayaraman V
Stargazin增强AMPA受体配体结合结构域的闭合，从而促进通道激活。跨膜AMPA受体（AMPAR）调节蛋白（TARPs）显著增强AMPAR功能，改变配体功效和受体门控动力学，从而形成突触后反应。然而，TARP对门控的影响的结构机制尚不清楚。在这里，我们发现TARP家族的原型成员stargazin或γ-2挽救了携带突变的AMPAR中的门控缺陷，这些突变破坏了配体结合结构域（LBD）的闭合裂隙状态，这表明stargazin逆转了这些突变的影响，并可能稳定了闭合LBD状态。此外，stargazin促进LBD的更封闭的构象，如通过减少对大拮抗剂NBQX的可及性所指示的。与功能研究一致，发光共振能量转移实验直接表明，在载脂蛋白和激动剂结合状态下，在stargazin存在下，AMPAR LBD平均更封闭。LBD的更多闭合裂隙状态的额外裂隙闭合和/或稳定预期转化为更高的激动剂功效，并且可能有助于stargazin调节AMPAR功能的结构机制。
Stargazin enhances closure of the AMPA receptor ligand-binding domain, thereby facilitating channel activation. Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) markedly enhance AMPAR function, altering ligand efficacy and receptor gating kinetics and thereby shaping the postsynaptic response. The structural mechanism underlying TARP effects on gating, however, is unknown. Here we find that the prototypical member of the TARP family, stargazin or γ-2, rescues gating deficits in AMPARs carrying mutations that destabilize the closed-cleft states of the ligand-binding domain (LBD), suggesting that stargazin reverses the effects of these mutations and likely stabilizes closed LBD states. Furthermore, stargazin promotes a more closed conformation of the LBD, as indicated by reduced accessibility to the large antagonist NBQX. Consistent with the functional studies, luminescence resonance energy transfer experiments directly demonstrate that the AMPAR LBD is on average more closed in the presence of stargazin, in both the apo and agonist-bound states. The additional cleft closure and/or stabilization of the more closed-cleft states of the LBD is expected to translate to higher agonist efficacy and could contribute to the structural mechanism for stargazin modulation of AMPAR function.
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影响因子：
5.3
作者：
Menuz, Karen;O'Brien, Jessica L.;Nicoll, Roger A.
通讯作者：
Nicoll, Roger A.
影响因子：
5.5
作者：
MacLean, David M.;Bowie, Derek
通讯作者：
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DOI：
10.1073/pnas.1037393100
发表时间：
2003-05-13
影响因子：
11.1
作者：
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通讯作者：
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DOI：
10.1073/pnas.0603225103
发表时间：
2006-07-05
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
16.2
作者：
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通讯作者：
Roux, Benoit