Physical and Analytical Chemistry Seminar
Lecturer: Nir Dayan
Location: Faculty Seminar Room
Amyloid fiber-forming proteins are predominantly intrinsically disordered proteins (IDPs). The protein tau, present mostly in neurons, is no exception. There is a significant interest in the study of tau protein aggregation mechanisms, given the direct correlation between the deposit of beta-sheet structured neurofibrillary tangles made of tau and pathology in several neurodegenerative diseases, including Alzheimer’s disease.
Among the core unresolved questions is the nature of the initial step triggering aggregation, with increasing attention placed on the question whether a conformational change of the IDPs plays a key role in the early stages of aggregation. Evidence show that a shift in the conformation ensemble of tau is involved in its aggregation pathway, and might even dictate structural and pathological properties of mature fibers. Yet, because IDPs lack a well-defined 3D structure and continuously exchange between different conformers, it has been technically challenging to characterize their structural changes on-pathway to aggregation.
Double spin labeling of the beta-sheet stacking region of tau combined with pulsed double electron–electron resonance spectroscopy is a powerful method to assay conformational changes occurring during the course of tau aggregation, by probing intramolecular distances around aggregation-prone domains. The potential of this approach was demonstrated by results on conformation rearrangement of the beta-sheet stacking segment VQIINK (known as PHF6*) of tau. This method should to be applicable to other critical segments of tau and other IDPs.