Shape-controlled molecular assembly and dynamic structural biology

Why study the aggregation pathway of Tau?

Scientists who know this field will be most skeptical given that protein aggregation appears to have been studied “forever”. Tau is an intrinsically disordered protein (IDP) that when misfolded forms specific conformations that define the largest family of neurodegenerative diseases, tauopathies, that include Alzheimer’s disease and Chronic Traumatic Encephalopathy (CTE). The controlled assembly pathway of Tau into these exact pathological structures are the core tool needed for the screening of medicinal compounds and other therapeutics.

What is the knowledge gap?

Shape-controlled assembly of tau into well-defined fibril phenotypes along a predicted aggregation pathway has never been achieved to date, despite the critical importance of replicating pathological tau fibril phenotypes. Reliably replicating aggregation pathways that reproduce pathological hallmarks is a necessary starting point for screening medicinal compounds and developing tauopathy therapeutics.

Han Lab Strategy?

The Han lab engages in serious collaboration with neuroscientists and clinical researchers to help advance the development of therapeutic strategies for tauopathies. However, the Han lab also knows that its role should be to come up with out of the box solution because the “obvious” approaches will have been tried and are being tested by thousands of researchers. The Han lab is uniquely focusing on establishing the “molecular grammar” of Tau protein assembly. That includes identifying a peptide motif that forms strand-loop-strand (SLS) structures in 4R Tauopathy fibrils and can in and of itself form fibrils that display “infectious prion” properties, as well as uncovering the molecular signatures that guide Tau into forming in register aggregation to neat fibrils with active ends that display templating property as found in prions. This property of seeding-active fibrils is well known but its molecular basis is not, which means that this property cannot be easily replicated in the laboratory until the design principle of tau prions are uncovered.

Unique Han Lab Tools and Concepts?

Our Focus on visualizing the entire dynamic assembly process from the ensemble structure of tau in its IDP state to the folded structure of the assembled tau fibrils relies on pulsed dipolar electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR) and Cryogenic Electron Microscopy (CRYO-EM) to reach Angstrom to 10 nm scale distances. Double Electron Electron Resonance (DEER) yields a probability distribution of intra-tau distances, P(r), and is the first go-to-step to gain first insight to the complete conformational ensemble of Tau in IDP and/or fibril state.

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