Dynamics and Interactions of GPI-Linked lynx1 Protein with/without Nicotinic Acetylcholine Receptor in Membrane Bilayers.
Dynamics and Interactions of GPI-Linked lynx1 Protein with/without Nicotinic Acetylcholine Receptor in Membrane Bilayers.
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DOI：
10.1021/acs.jpcb.0c00159
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发表时间：
2020-05-21
期刊：
影响因子：
--
通讯作者：
Im W
中科院分区：
文献类型：
--
作者：
Dong C;Kern NR;Anderson KR;Zhang XF;Miwa JM;Im W
烟碱型乙酰胆碱受体(NAChR)参与多种生物学过程，如情绪、学习和成瘾等。糖基磷脂酰肌醇(GPI)连接的lynx1是nAChR功能的变构调节剂，包括激动剂敏感性的改变，脱敏反应的降低，以及脱敏反应的缓慢恢复。这种调节被认为是通过Lynx1‘S与nAChR亚基的相互作用实现的，特别是在α4：α4接口。在这项研究中，我们使用分子建模和模拟来研究lynx1与nAChRs结合时的结构、动力学和相互作用，以及未结合的单体lynx1嵌入膜中时的结构、动力学和相互作用。尽管Lynx1的结构在两种状态下都是相似的，但Lynx1动力学在结合态比非结合态受到更多的限制。当绑定时，可以观察到lynx1和nAChR之间的相互作用在整个模拟过程中保持不变。特别要注意的是，Lynx1显示了与nAChRα4亚基之一的受体C-环的长时间相互作用，这是一个对激动剂结合以及可能在打开/关闭状态之间转换的重要区域。在与Lynx1的相互作用中，α4的C-环往往在关闭或打开状态下受到限制，而当nAChR被Lynx1解除结合时，C-环的状态转变更为明显。有趣的是，C-环的构象变化是随机的，这表明Lynx1可以影响nAChR(对其多峰作用至关重要)，例如通过改变其激动剂的敏感性和从脱敏中恢复。
Nicotinic acetylcholine receptor (nAChR) participates in diverse biological processes, e.g., mood, learning, and addiction. Glycosylphosphatidylinositol (GPI)-linked lynx1 is an allosteric modulator of nAChR function, including shifts in agonist sensitivity, reduced desensitization, and slower recovery from desensitization. This modulation is thought to be achieved by lynx1’s interaction with nAChR subunits, particularly at the α4:α4 interface. In this study, we used molecular modeling and simulation to study the structure, dynamics, and interactions of lynx1 when bound to nAChRs, as well as unbound, monomeric lynx1, when embedded in membranes. Though lynx1 structures are similar in both states, lynx1 dynamics are more restricted in the bound state than in the unbound one. When bound, interactions between lynx1 and nAChR are observed to be maintained throughout the simulations. Of particular note, lynx1 demonstrates prolonged interactions with the receptor C-loop in one of the nAChR α4 subunits, a region important for agonist binding and possibly the transition between open/close states. During interactions with lynx1, an α4 C-loop tends to be restricted in either close or open state, whereas the C-loop state transitions are more evident in when the nAChR is unbound by lynx1. Interestingly, the conformational change of the C-loop is stochastic, suggesting that lynx1 can influence nAChR (critical for its multimodal action), for instance by shifting its agonist sensitivity and recovery from desensitization.
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DOI：
10.1124/jpet.112.197871
发表时间：
2013-01-01
影响因子：
3.5
作者：
Freitas, Kelen;Carroll, F. Ivy;Damaj, M. Imad
通讯作者：
Damaj, M. Imad
影响因子：
8.6
作者：
Dion, M;Rydberg, H;Lundqvist, BI
通讯作者：
Lundqvist, BI
影响因子：
5.5
作者：
Guvench, Olgun;Hatcher, Elizabeth;Venable, Richard M.;Pastor, Richard W.;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
--
作者：
Dani JA
通讯作者：
Dani JA
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M