Differential phospholipid binding of alpha-synuclein variants implicated in Parkinson's disease revealed by solution NMR spectroscopy.
Differential phospholipid binding of alpha-synuclein variants implicated in Parkinson's disease revealed by solution NMR spectroscopy.
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DOI：
10.1021/bi901723p
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发表时间：
2010-02-09
期刊：
影响因子：
2.9
通讯作者：
Bax, Ad
中科院分区：
文献类型：
--
作者：
Bodner, Christina R.;Maltsev, Alexander S.;Dobson, Christopher M.;Bax, Ad
突触前蛋白α-突触核蛋白（αS）的三种家族性变体A30 P、E46 K和A53 T与罕见的遗传性帕金森病（PD）相关，而野生型αS与散发性PD有关。家族性和散发性PD的经典表现是αS纤维状结构的形成，其作为主要成分积聚在神经元内路易体中。在突触前末梢，αS在无序的胞质和膜结合状态之间的分配可能介导其在突触囊泡储备池调节中的作用。以前，我们报道了多种不同的磷脂结合模式的αS与缓慢的结合动力学。在这里，我们报告的磷脂结合特性的疾病的变种，通过溶液NMR在一个残基特异性的方式。我们的结果与以前的生物物理研究定性一致，引用了相对于野生型αS，A30 P突变的脂质亲和力总体降低，A53 T的亲和力相当，E46 K的结合水平增加。此外，我们的NMR结果描述了αS的脂质结合状态的分布：相对于野生型αS，SL 1结合模式（残基3−25结合为螺旋）的群体被每种疾病变体所增强。我们提出，SL 1结合模式，锚定在脂蛋白复合物中的αS的N-末端，而疏水性NAC区域保持动态无序，容易发生分子间相互作用，从而发展为疾病相关的寡聚体和原纤维。SL 1结合模式的升高（未被纳入完整N-末端结构域的结合模式的比例群体所抑制）可能很好地解释了αS的A30 P、E46 K和A53 T疾病变体的毒性增加。
Three familial variants of the presynaptic protein α-synuclein (αS), A30P, E46K, and A53T, correlate with rare inherited Parkinson’s disease (PD), while wild-type αS is implicated in sporadic PD. The classic manifestation of both familiar and sporadic PD is the formation of fibrillar structures of αS which accumulate as the main component in intraneuronal Lewy bodies. At presynaptic termini, the partitioning of αS between disordered cytosolic and membrane-bound states likely mediates its proposed role in regulation of reserve pools of synaptic vesicles. Previously, we reported on multiple distinct phospholipid binding modes of αS with slow binding kinetics. Here, we report the phospholipid binding properties of the disease variants, viewed by solution NMR in a residue-specific manner. Our results agree qualitatively with previous biophysical studies citing overall decreased lipid affinity for the A30P mutation, comparable affinity for A53T, and an increased level of binding of E46K, relative to wild-type αS. Additionally, our NMR results describe the distribution of lipid-bound states for αS: the population of the SL1 binding mode (residues 3−25 bound as a helix) is augmented by each of the disease variants, relative to wild-type αS. We propose that the SL1 binding mode, which anchors the N-terminus of αS in the lipoprotein complex while the hydrophobic NAC region remains dynamically disordered, is prone to intermolecular interactions which progress toward disease-associated oligomers and fibrils. The elevation of the SL1 binding mode, unchecked by a proportionate population of binding modes incorporating the full N-terminal domain, may well account for the increased toxicity of the A30P, E46K, and A53T disease variants of αS.
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DOI：
10.1073/pnas.0407146102
发表时间：
2005-02-01
影响因子：
11.1
作者：
Bertoncini, CW;Jung, YS;Zweckstetter, M
通讯作者：
Zweckstetter, M
影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
15
作者：
Igumenova, Tatyana I.;Palmer, Arthur G., III
通讯作者：
Palmer, Arthur G., III
影响因子：
2.9
作者：
Bussell, R;Eliezer, D
通讯作者：
Eliezer, D
DOI：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT