title: Domain conformation of tau protein studied by solution small-angle X-ray scattering.
abstract: Tau is one of the two main proteins involved in the pathology of Alzheimer's disease via formation of beta-sheet rich intracellular aggregates named paired helical filaments (PHFs). Given that tau is a natively unfolded protein with no folded core (even upon binding to physiological partners such as microtubules), its structural analysis by high-resolution techniques has been difficult. In this study, employing solution small-angle X-ray scattering from the full length isoforms and from a variety of deletion and point mutants the conformation of tau in solution is structurally characterized. A recently developed ensemble optimization method was employed to generate pools of random models and to select ensembles of coexisting conformations, which fitted simultaneously the scattering data from the full length protein and deletion mutants. The analysis of the structural properties of these selected ensembles allowed us to extract information about residual structure in different domains of the native protein. The short deletion mutants containing the repeat domain (considered the core constituent of the PHFs) are significantly more extended than random coils, suggesting an extended conformation of the repeat domain. The longer tau constructs are comparable in size with the random coils, pointing to long-range contacts between the N- and C-termini compensating for the extension of the repeat domain. Moreover, most of the aggregation-promoting mutants did not show major differences in structure from their wild-type counterparts, indicating that their increased pathological effect is triggered only after an aggregation core has been formed.
authors.affiliation: European Molecular Biology Laboratory, Hamburg Outstation, Notkestrasse 85, 22603 Hamburg, Germany.
authors.forename: Efstratios
authors.initials: E
authors.lastname: Mylonas
authors.forename: Antje
authors.initials: A
authors.lastname: Hascher
authors.forename: Pau
authors.initials: P
authors.lastname: Bernadó
authors.forename: Martin
authors.initials: M
authors.lastname: Blackledge
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry; D012996:Solutions; D014961:X-Ray Diffraction; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: C054369:MAPT protein, human; D020033:Protein Isoforms; D012996:Solutions; D016875:tau Proteins