Background/Aims: Alpha-synuclein (Î±-Syn) is a neuronal protein that is highly implicated in Parkinson's disease (PD), and protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that is associated with neurodegenerative diseases, such as PD. Î±-Syn can directly upregulate PP2A activity, but the underling mechanism remains unclear. Therefore, we investigated the molecular mechanism of Î±-Syn regulating PP2A activity. Methods: Î±-Syn and its truncations were expressed in E.coli, and purified by affinity chromatography. PP2A CÎ± and its mutants were expressed in recombinant baculovirus, and purified by affinity chromatography combined with gel filtration chromatography. The interaction between Î±-Syn and PP2A CÎ± was detected by GST pull-down assay. PP2A activity was investigated by the colorimetric assay. Results: The hydrophobic non-amyloid component (NAC) domain of Î±-Syn interacted with PP2A CÎ± and upregulated its activity. Î±-Syn aggregates reduced its ability to upregulate PP2A activity, since the hydrophobic domain of Î±-Syn was blocked during aggregation. Furthermore, in the hydrophobic center of PP2A CÎ±, the residue of I123 was responsible for PP2A to interact with Î±-Syn, and its hydrophilic mutation blocked its interaction with Î±-Syn as well as its activity upregulation by Î±-Syn. Conclusions: Î±-Syn bound to PP2A CÎ± by the hydrophobic interaction and upregulated its activity. Blocking the hydrophobic domain of Î±-Syn or hydrophilic mutation on the residue I123 in PP2A CÎ± all reduced PP2A activity upregulation by Î±-Syn. Overall, we explored the mechanism of Î±-Syn regulating PP2A activity, which might offer much insight into the basis underlying PD pathogenesis.
Cellular Physiology and Biochemistry
Digital Object Identifier (DOI)
Qu, Jing; Yan, Hongxia; Zheng, Yuan; Xue, Fenqin; Zheng, Yan; Fang, Hongjuan; Chang, Yongchang; Yang, Hui; and Zhang, Jianliang, "The Molecular Mechanism Of Alpha-Synuclein Dependent Regulation Of Protein Phosphatase 2A Activity" (2018). Neurobiology. 69.