期刊
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
卷 82, 期 9, 页码 1907-1923出版社
WILEY
DOI: 10.1002/prot.24544
关键词
tau protein; MAPT; microtubule; molecular dynamics; phosphorylation
资金
- iVEC
Aggregation of the microtubule associated protein tau (MAPT) within neurons of the brain is the leading cause of tauopathies such as Alzheimer's disease. MAPT is a phospho-protein that is selectively phosphorylated by a number of kinases in vivo to perform its biological function. However, it may become pathogenically hyperphosphorylated, causing aggregation into paired helical filaments and neurofibrillary tangles. The phosphorylation induced conformational change on a peptide of MAPT (htau(225-250)) was investigated by performing molecular dynamics simulations with different phosphorylation patterns of the peptide (pThr231 and/or pSer235) in different simulation conditions to determine the effect of ionic strength and phosphate charge. All phosphorylation patterns were found to disrupt a nascent terminal beta-sheet pattern ((226)VAVVR(230) and (244)QTAPVP(249)), replacing it with a range of structures. The double pThr231/pSer235 phosphorylation pattern at experimental ionic strength resulted in the best agreement with NMR structured charactierzation, with the observation of a transient alpha-helix ((239)AKSRLQT(245)). PPII helical conformations were only found sporadically throughout the simulations. (C) 2014 Wiley Periodicals, Inc.
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