Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR.
Interaction of Huntingtin Exon-1 Peptides with Lipid-Based Micellar Nanoparticles Probed by Solution NMR and Q-Band Pulsed EPR.
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DOI：
10.1021/jacs.8b02619
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发表时间：
2018-05-23
影响因子：
15
通讯作者：
Clore GM
中科院分区：
文献类型：
--
作者：
Ceccon A;Schmidt T;Tugarinov V;Kotler SA;Schwieters CD;Clore GM
基于脂质的胶束纳米颗粒促进亨廷顿蛋白外显子1肽的聚集。在此，我们利用核磁共振化学交换饱和转移（CEST）、圆二色性和脉冲Q波段电子顺磁共振（EPR）来表征两种此类肽（分别包含亨廷顿蛋白的N端两亲结构域以及7个和10个谷氨酰胺重复序列的httNTQ7和httNTQ10）与8纳米脂质胶束的相互作用。游离的和与胶束结合的httNTQn肽之间的交换在毫秒时间尺度上发生，解离常数（KD）约为0.5 - 1毫摩尔。在与胶束结合时，残基1 - 15采取螺旋构象。甲硫氨酸（Met）氧化为亚砜会使对胶束的结合亲和力降低约3 - 4倍，并使螺旋长度再增加两个残基。根据从CEST获得的胶束结合态的主链化学位移计算出结合的单体单元结构。脉冲Q波段EPR表明在胶束表面存在单体 - 二聚体平衡，并且二聚体的两个螺旋采取平行取向，从而使两个无序的多聚谷氨酰胺（polyQ）尾部紧密靠近，这可能会在从胶束表面解离时促进聚集。
Lipid-based micellar nanoparticles promote aggregation of huntingtin exon-1 peptides. Here we characterize the interaction of two such peptides, httNTQ7 and httNTQ10 comprising the N-terminal amphiphilic domain of huntingtin followed by 7 and 10 glutamine repeats, respectively, with 8 nm lipid micelles using NMR chemical exchange saturation transfer (CEST), circular dichroism and pulsed Q-band EPR. Exchange between free and micelle-bound httNTQn peptides occurs on the millisecond time scale with a KD ~ 0.5–1 mM. Upon binding micelles, residues 1–15 adopt a helical conformation. Oxidation of Met to a sulfoxide reduces the binding affinity for micelles ~3–4-fold and increases the length of the helix by a further two residues. A structure of the bound monomer unit is calculated from the backbone chemical shifts of the micelle-bound state obtained from CEST. Pulsed Q-band EPR shows that a monomer–dimer equilibrium exists on the surface of the micelles and that the two helices of the dimer adopt a parallel orientation, thereby bringing two disordered polyQ tails into close proximity which may promote aggregation upon dissociation from the micelle surface.
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影响因子：
3.4
作者：
Michalek, Matthias;Salnikov, Evgeniy S.;Bechinger, Burkhard
通讯作者：
Bechinger, Burkhard
影响因子：
4.7
作者：
Suopanki, J;Götz, C;Wanker, EE
通讯作者：
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影响因子：
13.3
作者：
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通讯作者：
Truant, Ray
DOI：
10.1073/pnas.0800256105
发表时间：
2008-03-25
影响因子：
11.1
作者：
Shen, Yang;Lange, Oliver;Bax, Ad
通讯作者：
Bax, Ad
影响因子：
2.9
作者：
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通讯作者：
Legleiter, Justin