Tau Aggregation Propensity Engrained in Its Solution State

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• 作者：Neil A. Eschmann ; Thanh D. Do ; Nichole E. LaPointe ; Joan-Emma Shea ; Stuart C. Feinstein ; Michael T. Bowers ; Songi Han
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：November 12, 2015
• 年：2015
• 卷：119
• 期：45
• 页码：14421-14432
• 全文大小：798K
• ISSN：1520-5207

文摘

A peptide fragment of the human tau protein which stacks to form neat cross 尾-sheet fibrils, resembling that found in pathological aggregation, ²⁷³GKVQIINKKLDL²⁸⁴ (here 鈥淩2/WT鈥?, was modified with a spin-label at the N-terminus. With the resulting peptide, R2/G273C-SL, we probed events at time scales spanning seconds to hours after aggregation is initiated using transmission electron microscopy (TEM), thioflavin T (THT) fluorescence, ion mobility mass spectrometry (IMMS), electron paramagnetic resonance (EPR), and Overhauser dynamic nuclear polarization (ODNP) to determine if deliberate changes to its conformational states and population in solution influence downstream propensity to form fibrillar aggregates. We find varying solution conditions by adding the osmolyte urea or TMAO, or simply using different buffers (acetate buffer, phosphate buffer, or water), produces significant differences in early monomer/dimer populations and conformations. Crucially, these characteristics of the peptide in solution state before aggregation is initiated dictate the fibril formation propensity after aggregation. We conclude the driving forces that accelerate aggregation, when heparin is added, do not override the subtle intra- or interprotein interactions induced by the initial solvent conditions. In other words, the balance of protein鈥損rotein vs protein鈥搒olvent interactions present in the initial solution conditions is a critical driving force for fibril formation.