Protein misfolding into amyloid fibrils is common in diseases as well as in pharmaceutical sciences. The latter refers to the phenomenon that peptide-based drugs often have the tendency to fibrillize, thus impeding solution formulation of the drug. Using solid-state NMR spectroscopy, we have investigated the structure and dynamics of two amyloid fibrils, one formed by the small peptide hormone glucagon and the other formed by the large microtubule-binding protein tau. Glucagon increases blood glucose level and is used to treat diabetic hypoglycemia, whereas tau misfolding into neurofibrillary tangles is found in many neurodegenerative diseases. Unexpectedly, solid-state NMR spectra reveal that the fibril formed by the small glucagon harbors two molecular conformations in a single fibril morphology, whereas the fibril formed by the large and dynamically disordered tau contains a monomorphic b-sheet core. The glucagon fibril consists of antiparallel rather than parallel hydrogen-bonded b-sheets, and has an unprecedented b-strand length of 10 nm. The 1.7 Å structure reveals many stabilizing interactions in the fibril, which suggest future strategies for designing glucagon analogs that resist fibril formation. For the 40 kDa full-length four-repeat tau, extensive multidimensional correlation solid-state NMR data show that the b-sheet core spans the second and third microtubule-binding repeats of the protein. The monomorphic nature of this heparin-fibrillized tau suggests that in-vitro tau fibrils may be good models for in-vivo tau aggregates. The domains outside the b-sheet core exhibit heterogeneous dynamics, some of which manifest b-sheet character. These results have tantalizing implications for the possible structure of four-repeat tau in four-repeat tau diseases such as progressive supranuclear palsy.

Structure and dynamics of glucagon and tau amyloid fibrils from solid-state NMR

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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