α-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356
α-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356
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DOI：
10.1074/jbc.274.36.25481
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发表时间：
1999-09-03
影响因子：
4.8
通讯作者：
Jakes, R
中科院分区：
文献类型：
--
作者：
Jensen, PH;Hager, H;Jakes, R
基于α-突触核蛋白中的错义突变与常染色体显性帕金森病的直接联系及其在路易样病变中的存在，α-突触核蛋白与几种神经变性疾病的发病机制有关。为了深入了解α-突触核蛋白的功能，我们研究了它是否结合神经元蛋白并调节其功能状态。通过人脑胞质溶胶的α-突触核蛋白亲和层析将微管相关蛋白tau鉴定为配体。使用I-125标记的人tau 40的直接结合测定证明了可逆结合，IC 50约为50 pM。通过蛋白质片段化和重组肽的使用确定，相互作用结构域定位于α-突触核蛋白的C末端和tau的微管结合区。高浓度的微管蛋白抑制tau蛋白和α-突触核蛋白之间的结合。在功能上，α-突触核蛋白刺激蛋白激酶A催化的tau丝氨酸残基262和356的磷酸化，如使用磷酸化表位特异性抗体所确定的。我们认为，α-突触核蛋白调节可溶性轴突tau蛋白的磷酸化，从而间接影响轴突微管的稳定性。
alpha-Synuclein has been implicated in the pathogenesis of several neurodegenerative disorders based on the direct linking of missense mutations in alpha-synuclein to autosomal dominant Parkinson's disease and its presence in Lewy-like lesions. To gain insight into alpha-synuclein functions, we have investigated whether it binds neuronal proteins and modulates their functional state. The microtubule-associated protein tau was identified as a ligand by alpha-synuclein affinity chromatography of human brain cytosol, Direct binding assays using I-125-labeled human tau40 demonstrated a reversible binding with a IC50 about 50 pM. The interacting domains were localized to the C terminus of alpha-synuclein and the microtubule binding region of tau as determined by protein fragmentation and the use of recombinant peptides. High concentrations of tubulin inhibited the binding between tau and alpha-synuclein. Functionally, a-synuclein stimulated the protein kinase A-catalyzed phosphorylation of tau serine residues 262 and 356 as determined using a phospho-epitope-specific antibody. We propose that alpha-synuclein modulates the phosphorylation of soluble axonal tau and thereby indirectly affects the stability of axonal microtubules.