Effect of altered solution conditions on tau conformational dynamics: Plausible implication on order propensity and aggregation

• Published in: Biochimica et biophysica acta. Proteins and proteomics 2018-05, Vol.1866 (5-6), p.668-679
• Main Authors: Jebarupa, Benita, Muralidharan, Monita, Srinivasu, Bindu Y., Mandal, Amit Kumar, Mitra, Gopa
• Format: Article
• Language: English
• Subjects: Conformational dynamics; Fibrillation; Humans; Intact mass spectrometry; Intrinsically disordered protein; Intrinsically Disordered Proteins - chemistry; Intrinsically Disordered Proteins - genetics; Limited proteolysis; Osmolar Concentration; Protein Aggregates; Protein Aggregation, Pathological; Protein Conformation; Protein Stability; Proteolysis; Recombinant Proteins - chemistry; Solvents - chemistry; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Tau; tau Proteins - chemistry; tau Proteins - genetics; Temperature
• ISSN: 1570-9639; 1878-1454
• DOI: 10.1016/j.bbapap.2018.04.004

Intrinsically disordered protein tau plays a central role in maintaining neuronal network by stabilizing microtubules in axon. Tau reportedly possesses random coil architecture, which is largely inert to alteration in solution conditions. However, the presence of transient compact conformers and residual structure has been evident from previous reports. Also, during Alzheimer's disease, misfolded tau detaches from microtubule and forms ordered filaments, which is the hallmark of the disease. Despite its fundamental role in neuronal physiology and in pathological cascade of several fatal neurodegenerative diseases, tau conformational dynamics remains poorly understood. In the present study, we have explored the effect of ionic strength, temperature and solvent polarity on tau40 conformational preferences using ion mobility mass spectrometry. Investigation of collision cross section revealed that while low ionic strength, elevated temperature and reduced solvent polarity mostly induced partial collapse in tau40 conformers, higher ionic strength led to an expansion of the molecule. Limited proteolysis identified segments of tau40 projection domain and proline-rich region having high order propensity and a C-terminal region having vulnerability for further expansion at altered solution conditions. The high susceptibility for disorder-to-order transition in the above region of the protein might have crucial implication on its role as microtubule spacers, and in cellular signaling cascade. The conformational adaptation of tau40 did not enhance the heparin-induced aggregation proclivity of the protein. Nevertheless, the observed correlation of electrostatic interaction with fibrillation propensity of tau40 might indicate plausible link between hyperphosphorylation at diseased state with tau conformation and self-assembly. •Conformational dynamics of unfolded protein tau is sensitive to solution conditions.•Depending on ionic strength, tau molecule can collapse or expand further.•Elevated temperatures and reduced solvent polarity lead to partial collapse in tau.•Projection domain and proline rich region of tau are highly susceptible to collapse.•Ionic interaction plays most important role in tau fibrillation.