期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 433, 期 22, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2021.167254
关键词
Tau; PET-FCS; Microsecond mixing; Conformational selection; Amyloid fibril
资金
- J. C. Bose National Research Fellowship from the Government of India
- IISER, Pune
- Department of Biotechnology, Government of India
Tau protein fragment tau-K18 undergoes a disorder to order transition in the presence of lipid micelles and vesicles, forming helical structures induced by a phospholipid mimetic. It has been shown that the mechanism of helical structure formation involves an intermediate state I, which can further progress to form a final helical state with a time constant of 50-200 microseconds. The helical conformation is found to be an aggregation-competent state that can lead to the formation of amyloid fibrils.
Tau is an intrinsically disordered protein implicated in many neurodegenerative diseases. The repeat domain fragment of tau, tau-K18, is known to undergo a disorder to order transition in the presence of lipid micelles and vesicles, in which helices form in each of the repeat domains. Here, the mechanism of helical structure formation, induced by a phospholipid mimetic, sodium dodecyl sulfate (SDS) at sub-micellar concentrations, has been studied using multiple biophysical probes. A study of the conformational dynamics of the disordered state, using photoinduced electron transfer coupled to fluorescence correlation spectroscopy (PET-FCS) has indicated the presence of an intermediate state, I, in equilibrium with the unfolded state, U. The cooperative binding of the ligand (L), SDS, to I has been shown to induce the formation of a compact, helical intermediate (IL5) within the dead time (similar to 37 mu s) of a continuous flow mixer. Quantitative analysis of the PET-FCS data and the ensemble microsecond kinetic data, suggests that the mechanism of induction of helical structure can be described by a U <-> I <-> IL5 <-> FL5 mechanism, in which the final helical state, FL5, forms from IL5 with a time constant of 50-200 mu s. Finally, it has been shown that the helical conformation is an aggregation-competent state that can directly form amyloid fibrils. (C) 2021 Elsevier Ltd. All rights reserved.
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