Side chain-dependent stacking modulates tau filament structure.

Martin Margittai; Ralf Langen

doi:10.1074/jbc.m605336200

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PubMed · 17023423

Side chain-dependent stacking modulates tau filament structure.

Martin Margittai·Ralf Langen

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Abstract

The misfolding of proteins into highly ordered fibrils with similar physical properties is a hallmark of many degenerative diseases. Here, we use the microtubule associated protein tau as a model system to investigate the role of amino acid side chains in the formation of such fibrils. We identify a region (positions 272-289) in the tau protein that, in the fibrillar state, either forms part of a core of parallel, in-register, beta-strands, or remains unfolded. Single point mutations are sufficient to control this conformational switch with disease mutants G272V and DeltaK280 (found in familial forms of dementia) inducing a folded state. Through systematic mutagenesis we derive a propensity scale for individual amino acids to form fibrils with parallel, in-register, beta-strands. This scale should not only apply to tau fibrils but generally to all fibrils with same strand arrangement.

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Amino Acid Sequence Amino Acid Substitution Dementia Electron Spin Resonance Spectroscopy Humans In Vitro Techniques Microscopy, Electron Models, Molecular Molecular Sequence Data Multiprotein Complexes Mutagenesis, Site-Directed Point Mutation Protein Conformation Protein Folding Protein Structure, Secondary Recombinant Proteins tau Proteins Journal Article Research Support, Non-U.S. Gov't

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Martin Margittai, Ralf Langen. 2006-10-05. Side chain-dependent stacking modulates tau filament structure.. https://doi.org/10.1074/jbc.m605336200

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