Proteins can aggregate to form cross-b amyloid fibrils under a wide variety of conditions, including in human brains over decades and in pharmaceutical formulations over hours or days. Elucidating the structural assembly and amino acid sequence determinants for amyloid formation is important for treating and preventing diseases as well as for producing more shelf-stable pharmaceutical compounds. In this talk I will describe the structure and dynamics of two amyloid-forming proteins, the microtubule-binding tau, which is involved in many neurodegenerative diseases, and the peptide hormone glucagon, which is used as an anti-hypoglycemia drug. Using solid-state NMR, we have investigated the global three-dimensional fold and the dynamics of heparin-fibrillized tau, and have obtained a high-resolution structure of glucagon fibrils. 1) Using multidimensional MAS NMR experiments, we have analyzed the three-dimensional fold of full-length tau proteins that include four and three microtubule-binding repeats (4R and 3R tau). The results show that <i>in vitro</i> 4R and 3R tau fibrils each adopts a single molecular conformation for the b-sheet core, and this conformation has significant resemblances with the tertiary structures of brain-derived tau fibrils. Thus, despite the presence of intrinsically disordered segments in this large protein, a predominant low-energy conformation appears to exist for the b-sheet core of the intact protein. 2) Using pharmaceutically relevant concentration and pH, we determined a 1.7 Å structure of the glucagon amyloid. The peptide assembles into a unique antiparallel hydrogen-bonded cross-b fibril with two coexisting b-strand conformations. The structure reveals many polar interactions that stabilize this fold, and suggests glucagon analogs that can inhibit fibril formation while retaining biological function.

Structure and dynamics of tau and glucagon amyloid fibrils from NMR

ACS Spring Meeting 2021

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