Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein
Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein
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DOI：
10.1073/pnas.0407146102
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发表时间：
2005-02-01
影响因子：
11.1
通讯作者：
Zweckstetter, M
中科院分区：
文献类型：
--
作者：
Bertoncini, CW;Jung, YS;Zweckstetter, M
在特发性帕金森病中，含有蛋白质α-突触核蛋白（α S）的聚集体的胞浆内神经元包涵体（路易体）沉积在脑干的色素核中。无害的，可能是天然展开的，aS的结构转变为神经毒性形式的机制在很大程度上是未知的。使用顺磁弛豫增强和NMR偶极耦合，我们表明，单体aS假设构象是稳定的长程相互作用，并采取行动，以抑制低聚和聚集。自抑制构象在纳秒至微秒的范围内波动，对应于折叠过程中二级结构形成的时间尺度。多胺结合和/或温度升高，诱导体外聚集的条件，释放这种固有的三级结构，导致容易缔合的完全未折叠构象。α S的天然自抑制结构的稳定化构成了减少或抑制帕金森病中的寡聚化和聚集的潜在策略。
In idiopathic Parkinson's disease, intracytoplasmic neuronal inclusions (Lewy bodies) containing aggregates of the protein a-synuclein (alphaS) are deposited in the pigmented nuclei of the brainstem. The mechanisms underlying the structural transition of innocuous, presumably natively unfolded, aS to neurotoxic forms are largely unknown. Using paramagnetic relaxation enhancement and NMR dipolar couplings, we show that monomeric aS assumes conformations that are stabilized by long-range interactions and act to inhibit oligomerization and aggregation. The autoinhibitory conformations fluctuate in the range of nanoseconds to microseconds corresponding to the time scale of secondary structure formation during folding. Polyamine binding and/or temperature increase, conditions that induce aggregation in vitro, release this inherent tertiary structure, leading to a completely unfolded conformation that associates readily. Stabilization of the native, autoinhibitory structure of alphaS constitutes a potential strategy for reducing or inhibiting oligomerization and aggregation in Parkinson's disease.