Nicotinic receptor interloop proline anchors beta1-beta2 and Cys loops in coupling agonist binding to channel gating.
Nicotinic receptor interloop proline anchors beta1-beta2 and Cys loops in coupling agonist binding to channel gating.
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DOI：
10.1085/jgp.200810014
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发表时间：
2008-08
影响因子：
3.8
通讯作者：
Sine, Steven M.
中科院分区：
文献类型：
--
作者：
Lee, Won Yong;Free, Chris R.;Sine, Steven M.
烟碱型乙酰胆碱受体（AChRs）介导整个外周和中枢神经系统的快速兴奋性突触传递。他们研究了神经释放的ACh与内源性通道开放的结合，但转导的结构基础尚未完全了解。先前的研究揭示了一个主要的转导途径，其中前M1结构域的αArg 209和β1-β2环的αGlu 45功能性地连接这两个区域，将β1-β2环的α瓦尔46定位在由αPro 272通过M2-M3环的αSer 269形成的空腔中。在这里，我们调查的贡献内和接近这一途径的残基使用单通道动力学分析，定点突变，和热力学突变周期分析。我们发现，在对通道门控的贡献中，标志性Cys环的α瓦尔46和α瓦尔132与αPro 272能量耦合。此外，这些残基在其大小和疏水性方面都进行了优化，以介导快速有效的通道门控，这表明在这些位置处天然存在的取代能够在Cys环受体超家族中实现不同范围的门控速率常数。总体结果表明，αPro 272功能性地偶联至ACh结合至通道开放转导途径内的从β1-β2和Cys环延伸的侧翼瓦尔残基。
Nicotinic acetylcholine receptors (AChRs) mediate rapid excitatory synaptic transmission throughout the peripheral and central nervous systems. They transduce binding of nerve-released ACh into opening of an intrinsic channel, yet the structural basis underlying transduction is not fully understood. Previous studies revealed a principal transduction pathway in which αArg 209 of the pre-M1 domain and αGlu 45 of the β1–β2 loop functionally link the two regions, positioning αVal 46 of the β1–β2 loop in a cavity formed by αPro 272 through αSer 269 of the M2–M3 loop. Here we investigate contributions of residues within and proximal to this pathway using single-channel kinetic analysis, site-directed mutagenesis, and thermodynamic mutant cycle analysis. We find that in contributing to channel gating, αVal 46 and αVal 132 of the signature Cys loop couple energetically to αPro 272. Furthermore, these residues are optimized in both their size and hydrophobicity to mediate rapid and efficient channel gating, suggesting naturally occurring substitutions at these positions enable a diverse range of gating rate constants among the Cys-loop receptor superfamily. The overall results indicate that αPro 272 functionally couples to flanking Val residues extending from the β1–β2 and Cys loops within the ACh binding to channel opening transduction pathway.
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影响因子：
64.5
作者：
CARTER, PJ;WINTER, G;FERSHT, AR
通讯作者：
FERSHT, AR
影响因子：
56.9
作者：
HIDALGO, P;MACKINNON, R
通讯作者：
MACKINNON, R
影响因子：
11.4
作者：
Hansen, SB;Sulzenbacher, G;Bourne, Y
通讯作者：
Bourne, Y
DOI：
10.1073/pnas.0406777102
发表时间：
2005-01-04
影响因子：
11.1
作者：
Chakrapani, S;Auerbach, A
通讯作者：
Auerbach, A
影响因子：
3.6
作者：
Gao, Fan;Mer, Georges;Sine, Steven M.
通讯作者：
Sine, Steven M.