title: A Two-Component Adhesive: Tau Fibrils Arise from a Combination of a Well-Defined Motif and Conformationally Flexible Interactions.
abstract: Fibrillar aggregates of Aβ and Tau in the brain are the major hallmarks of Alzheimer's disease. Most Tau fibers have a twisted appearance, but the twist can be variable and even absent. This ambiguity, which has also been associated with different phenotypes of tauopathies, has led to controversial assumptions about fibril constitution, and it is unclear to-date what the molecular causes of this polymorphism are. To tackle this question, we used solid-state NMR strategies providing assignments of non-seeded three-repeat-domain Tau3RDwith an inherent heterogeneity. This is in contrast to the general approach to characterize the most homogeneous preparations by construct truncation or intricate seeding protocols. Here, carbon and nitrogen chemical-shift conservation between fibrils revealed invariable secondary-structure properties, however, with inter-monomer interactions variable among samples. Residues with variable amide shifts are localized mostly to N- and C-terminal regions within the rigid beta structure in the repeat region of Tau3RD. By contrast, the hexapeptide motif in repeat R3, a crucial motif for fibril formation, shows strikingly low variability of all NMR parameters: Starting as a nucleation site for monomer-monomer contacts, this six-residue sequence element also turns into a well-defined structural element upon fibril formation. Given the absence of external causes in vitro, the interplay of structurally differently conserved elements in this protein likely reflects an intrinsic property of Tau fibrils.
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Shengqi
authors.initials: S
authors.lastname: Xiang
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Kulminskaya
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.|Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux/CBMN UMR5248 , 2 rue Robert Escarpit, 33600 Pessac, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Habenstein
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|CAESAR Research Center , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|CAESAR Research Center , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Tepper
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Paulat
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Griesinger
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Becker
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.|Institut für Biologie, Humboldt-Universität zu Berlin , Invalidenstrasse 110, 10115 Berlin, Germany.|Department of Molecular Biophysics, Leibniz-Institut für Molekulare Pharmakologie (FMP) , Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Lange
authors.affiliation: DZNE, German Center for Neurodegenerative Diseases , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|CAESAR Research Center , Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.|Hamburg Outstation, c/o DESY, Max-Planck-Institute for Metabolism Research , Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.affiliation: Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry , Am Fassberg 11, 37077 Göttingen, Germany.|Department Chemistry and Pharmacy, Ludwig-Maximilians-University Munich , Butenandtstrasse 5-13, 81377 Munich, Germany.
authors.forename: Rasmus
authors.identifier: 0000-0001-8983-2935
authors.initials: R
authors.lastname: Linser
mesh_terms: D000269:Adhesives / Q000737:chemistry*; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D000269:Adhesives; D008565:Membrane Proteins; D016875:tau Proteins; C054369:MAPT protein, human