title: Side chain-dependent stacking modulates tau filament structure.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Margittai
authors.forename: Ralf
authors.initials: R
authors.lastname: Langen
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure
chemical_list: C054369:MAPT protein, human; D046912:Multiprotein Complexes; D011994:Recombinant Proteins; D016875:tau Proteins