O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding.
O-GlcNAcylation of α-Synuclein at Serine 87 Reduces Aggregation without Affecting Membrane Binding.
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DOI：
10.1021/acschembio.7b00113
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发表时间：
2017-04-21
影响因子：
4
通讯作者：
Pratt MR
中科院分区：
文献类型：
--
作者：
Lewis YE;Galesic A;Levine PM;De Leon CA;Lamiri N;Brennan CK;Pratt MR
神经退行性疾病相关蛋白的聚集可受多种因素影响，包括多种翻译后修饰。其中一种修饰，O-GlcNAc酰化，已经在这些聚集倾向蛋白中的一些上发现，包括α-突触核蛋白，其是在突触核蛋白病如帕金森病中起致病作用的主要蛋白。我们先前使用合成蛋白质化学来制备在苏氨酸72处具有均一O-GlcNAc修饰的α-突触核蛋白，并且表明该修饰抑制蛋白质聚集。然而，已经确定的其他八个O-GlcNAc化位点的影响是未知的。在这里，我们使用类似的合成策略来研究这些位点之一丝氨酸87处的这种修饰的后果。我们表明，在这个网站上的O-GlcNAc化也抑制α-突触核蛋白聚集，但在较小程度上比相同的修改在苏氨酸72。然而，我们还发现这种修饰并不影响α-突触核蛋白的膜结合特性，这将其与同一位点的磷酸化区分开来。这些结果进一步支持开发可以提高α-突触核蛋白的O-GlcNAc酰化以减缓帕金森病进展的疗法。
The aggregation of neurodegenerative-disease associated proteins can be affected by many factors, including a variety of post-translational modifications. One such modification, O-GlcNAcylation, has been found on some of these aggregation prone proteins, including α-synuclein, the major protein that plays a causative role in synucleinopathies like Parkinson’s disease. We previously used synthetic protein chemistry to prepare α-synuclein bearing a homogeneous O-GlcNAc modification at threonine 72 and showed that this modification inhibits protein aggregation. However, the effects of the other eight O-GlcNAcylation sites that have been identified were unknown. Here, we use a similar synthetic strategy to investigate the consequences of this modification at one of these sites, serine 87. We show that O-GlcNAcylation at this site also inhibits α-synuclein aggregation but to a lesser extent than that for the same modification at threonine 72. However, we also find that this modification does not affect the membrane-binding properties of α-synuclein, which differentiates it from phosphorylation at the same site. These results further support the development of therapies that can elevate O-GlcNAcylation of α-synuclein to slow the progression of Parkinson’s disease.
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DOI：
10.1073/pnas.1512876113
发表时间：
2016-02-16
影响因子：
11.1
作者：
Fares, Mohamed-Bilal;Maco, Bohumil;Lashuel, Hilal A.
通讯作者：
Lashuel, Hilal A.
影响因子：
7.7
作者：
Wang, Zihao;Park, Kyoungsook;Comer, Frank;Hsieh-Wilson, Linda C.;Saudek, Christopher D.;Hart, Gerald W.
通讯作者：
Hart, Gerald W.
DOI：
10.1083/jcb.201501101
发表时间：
2015-03-30
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bond MR;Hanover JA
通讯作者：
Hanover JA
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：
5.3
作者：
O'Donnell, N;Zachara, NE;Marth, JD
通讯作者：
Marth, JD