Adding hydrophobicity or positive charges to the cytosolic half of the α-synuclein 3-11 helix increases membrane association and S129 phosphorylation.
Adding hydrophobicity or positive charges to the cytosolic half of the α-synuclein 3-11 helix increases membrane association and S129 phosphorylation.
复制标题
添加疏水性或正电荷到 α-突触核蛋白 3-11 螺旋的胞质一半会增加膜结合和 S129 磷酸化。
DOI：
10.1002/1873-3468.14773
复制
发表时间：
2024
期刊：
影响因子：
3.5
通讯作者：
Dettmer,Ulf
中科院分区：
文献类型：
--
作者：
Shimanaka,Kazuma;Shi,Bryan;Brontesi,Lisa;Alnakhala,Heba;Jayanthi,Vidyashree;Subramanian,Kanagaraj;Ramalingam,Nagendran;Tripathi,Arati;Dettmer,Ulf
神经元蛋白 α-突触核蛋白主要参与帕金森病和相关突触核蛋白病中发生的神经变性。 α-突触核蛋白的膜诱导的 3-11 螺旋构象具有疏水性膜嵌入一半和亲水性胞质一半。在这里，我们研究了 (a) 胞质暴露螺旋第 8 位氨基酸令人惊讶的疏水性的重要性； (b) 所有胞质暴露位置 (1-5-8-9) 均不存在带正电的赖氨酸/精氨酸。我们发现 (a) 进一步增加疏水性或在第 8 位添加赖氨酸而不是谷氨酸会增强膜相互作用和 S129 磷酸化； (b) 在胞质暴露位置 1、5、8 或 9 添加赖氨酸具有类似的效果。通过生化分级分离，膜中大量存在的变体在免疫荧光显微镜下与转铁蛋白受体（一种内体标记物）明显共定位，表明在囊泡膜上积累。因此，我们观察到膜吸引力和 S129 磷酸化之间存在显着的相关性，这对于理解健康和疾病中的 α-突触核蛋白生物学相关。
The neuronal protein α‐synuclein is centrally involved in the neurodegeneration occurring in Parkinson's disease and related synucleinopathies. α‐Synuclein's membrane‐induced 3–11 helix conformation has a hydrophobic membrane‐embedded half and a hydrophilic cytosolic half. Here, we studied the significance of (a) the surprising hydrophobicity of amino‐acids at cytosol‐exposed helix position 8; (b) the absence of positively charged lysine/arginine from all cytosol‐exposed positions (1‐5‐8‐9). We found that (a) further increasing hydrophobicity or adding lysine, but not glutamate, at position 8 augments both membrane interaction and S129 phosphorylation; (b) adding lysines at cytosol‐exposed positions 1, 5, 8, or 9 has similar effects. Variants abundantly present in membranes by biochemical fractionation markedly colocalized with transferrin‐receptor (an endosomal marker) in immunofluorescence‐microscopy, indicating accumulation at vesicle membranes. Thus, we observed a striking correlation between membrane attraction and S129 phosphorylation, relevant for understanding α‐synuclein biology in health and disease.