Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants.-猫眼课题宝

DOI：

10.1021/jp801175w

发表时间：

2008-09-04

期刊：

The journal of physical chemistry. B

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

Grabenauer M;Bernstein SL;Lee JC;Wyttenbach T;Dupuis NF;Gray HB;Winkler JR;Bowers MT

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639767/?report=classic

α-突触核蛋白（α-syn）是一种与帕金森病（PD）有关的蛋白质，其聚集被认为是通过形成部分折叠的中间体来进行的。利用纳米电喷雾电离（ESI）质谱法结合离子迁移率测量，我们发现α-syn及其疾病相关的A53T突变体具有高度紧凑的部分折叠结构家族，净电荷为- 6、- 7和- 8。对于另一个早发性PD突变体A30P，只有当蛋白的净电荷为- 6时，这种高度紧密的群体才明显。当与精胺结合在接近生理pH值时，所有三种蛋白质都经历了电荷减少，从有利的溶液电荷状态- 10降至净电荷- 6。这种电荷的减少伴随着大约两倍的尺寸的急剧减小（2600Å2（−10电荷态）的横截面下降到1430Å2（−6电荷态））。我们得出结论，精胺通过诱导α-syn的坍塌构象来提高α-syn的聚集率，然后继续形成聚集体。

The aggregation of α-synuclein (α-syn), a protein implicated in Parkinson’s disease (PD), is believed to progress through the formation of a partially folded intermediate. Using nano-electrospray ionization (ESI) mass spectrometry combined with ion mobility measurements we found evidence for a highly compact partially folded family of structures for α-syn and its disease-related A53T mutant with net charges of −6, −7 and −8. For the other early-onset PD mutant, A30P, this highly compact population was only evident when the protein had a net charge of −6. When bound to spermine near physiologic pH, all three proteins underwent a charge reduction from the favored solution charge state of −10 to a net charge of −6. This charge reduction is accompanied by a dramatic size reduction of about a factor of two (cross section of 2600Å2 (−10 charge state) down to 1430Å2 (−6 charge state)). We conclude that spermine increases the aggregation rate of α-syn by inducing a collapsed conformation, which then proceeds to form aggregates.