Membrane remodeling by α-synuclein and effects on amyloid formation.
Membrane remodeling by α-synuclein and effects on amyloid formation.
复制标题
DOI：
10.1021/ja405993r
复制
发表时间：
2013-10-30
影响因子：
15
通讯作者：
Lee JC
中科院分区：
文献类型：
--
作者：
Jiang Z;de Messieres M;Lee JC
α-突触核蛋白(α-Syn)是一种内在紊乱的蛋白质，与帕金森氏症有关。虽然分子致病机制尚不清楚，但越来越多的证据将其淀粉样蛋白形成和膜结合倾向与疾病病因联系起来。与最近的数据显示α-SYN的膜重塑涉及阴离子磷脂和螺旋结构相反，我们发现该蛋白将表面没有净电荷的囊泡(磷脂酰胆碱，PC)变形为平均直径~20 nm的小管。圆二色谱未检测到添加囊泡后可辨别的二级结构变化。值得注意的是，膜重塑抑制α-SYN淀粉样蛋白的形成，影响停滞期和生长期。利用5种单一色氨酸异构体和时间分辨荧光各向异性测量，我们确定α-SYN对双层结构的影响具有惊人的弱相互作用和无位置特异性(分配常数，Kp~300M−1)。用透射电子显微镜表征了α-SYN在各种不同脂质/蛋白质条件下的囊泡变形。由于细胞膜富含PC脂类，这些结果支持α-SYN诱导的膜重塑可能的生物学后果，与功能和发病机制有关。
α-Synuclein (α-Syn), an intrinsically disordered protein, is associated with Parkinson’s disease. Though molecular pathogenic mechanisms are ill-defined, mounting evidence connects its amyloid forming and membrane binding propensities to disease etiology. Contrary to recent data suggesting that membrane remodeling by α-syn involves anionic phospholipids and helical structure, we discovered that the protein deforms vesicles with no net surface charge (phosphatidylcholine, PC) into tubules (average diameter ~ 20 nm). No discernible secondary structural changes were detected by circular dichroism spectroscopy upon the addition of vesicles. Notably, membrane remodeling inhibits α-syn amyloid formation affecting both lag and growth phases. Using five single-tryptophan variants and time-resolved fluorescence anisotropy measurements, we determined that α-syn influences bilayer structure with surprisingly weak interaction and no site specificity (partition constant, Kp ~ 300 M−1). Vesicle deformation by α-syn under a variety of different lipid/protein conditions is characterized via transmission electron microscopy. As cellular membranes are enriched in PC lipids, these results support possible biological consequences for α-syn induced membrane remodeling related to both function and pathogenesis.
登录
查看更多内容
影响因子：
2.9
作者：
Maltsev AS;Ying J;Bax A
通讯作者：
Bax A
影响因子：
3.3
作者：
Pandey, Anjan P.;Haque, Farzin;Rochet, Jean-Christophe;Hovis, Jennifer S.
通讯作者：
Hovis, Jennifer S.
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
4.8
作者：
Mizuno, Naoko;Varkey, Jobin;Steven, Alasdair C.
通讯作者：
Steven, Alasdair C.
影响因子：
4.8
作者：
Nakamura, Ken;Nemani, Venu M.;Edwards, Robert H.
通讯作者：
Edwards, Robert H.