Helix periodicity, topology, and dynamics of membrane-associated α-Synuclein
Helix periodicity, topology, and dynamics of membrane-associated α-Synuclein
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DOI：
10.1110/ps.041255905
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发表时间：
2005-04-01
期刊：
影响因子：
8
通讯作者：
Eliezer, D
中科院分区：
文献类型：
--
作者：
Bussell, R;Ramlall, TF;Eliezer, D
蛋白质α-突触核蛋白（aS）是突触强度和多巴胺稳态的突触囊泡相关调节剂，在帕金森病中具有病理作用。aS的正常功能取决于与带负电荷的脂质表面结合时所采用的膜相关构象。以前，我们发现，膜结合域的aS是螺旋，并建议它可能表现出不寻常的结构周期性。在这里，我们提出了一个研究的周期性，拓扑结构和动力学的洗涤剂胶束结合的aS使用顺磁性自旋标签嵌入在胶束中或连接到蛋白质。我们发现，螺旋区的aS完成三个完整的转折，每11个残基，证明了建议的11/3周期性。我们还发现，膜结合域是部分埋在胶束表面和弯曲的疏水内部，但不穿越胶束。胶束内的某些区域，包括独特的无赖氨酸第六个11-残基重复，更深的浸没，观察到，可能是功能上重要的。有没有长距离的第三次接触在这个域，表明一个高度扩展的配置。胶束结合区域的骨架动力学是相对均匀的，朝向C-末端观察到的灵活性略有下降。这些结果阐明了与膜模拟洗涤剂胶束结合的aS的拓扑特征，对aS功能和病理学具有影响。
The protein alpha-Synuclein (aS) is a synaptic vesicle-associated regulator of synaptic strength and dopamine homeostasis with a pathological role in Parkinson's disease. The normal function of aS depends on a membrane-associated conformation that is adopted upon binding to negatively charged lipid surfaces. Previously we found that the membrane-binding domain of aS is helical and suggested that it may exhibit an unusual structural periodicity. Here we present a study of the periodicity, topology, and dynamics of detergent micelle-bound aS using paramagnetic spin labels embedded in the micelle or attached to the protein. We show that the helical region of aS completes three full turns every 11 residues, demonstrating the proposed 11/3 periodicity. We also find that the membrane-binding domain is partially buried in the micelle surface and bends toward the hydrophobic interior, but does not traverse the micelle. Deeper submersion of certain regions within the micelle, including the unique lysine-free sixth 11-residue repeat, is observed and may be functionally important. There are no long-range tertiary contacts within this domain, indicating a highly extended configuration. The backbone dynamics of the micelle-bound region are relatively uniform with a slight decrease in flexibility observed toward the C-terminal end. These results clarify the topological features of aS bound to membrane-mimicking detergent micelles, with implications for aS function and pathology.