title: Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein.
abstract: The microtubule-associated tau proteins represent a family of closely related phosphoproteins that become enriched in the axons during brain development. In Alzheimer's disease (AD), tau aggregates somatodendritically in paired helical filaments in a hyperphosphorylated form. Most of the sites that are phosphorylated to a high extent in paired helical filament tau are clustered in the proline-rich region (P-region; residues 172--251) and the C-terminal tail region (C-region; residues 368--441) that flank tau's microtubule-binding repeats. This might point to a role of a region-specific phosphorylation cluster for the pathogenesis of AD. To determine the functional consequences of such modifications, mutated tau proteins were produced in which a P- or C-region-specific phosphorylation cluster was simulated by replacement of serine/threonine residues with glutamate. We show that a phosphorylation-mimicking glutamate cluster in the P-region is sufficient to block microtubule assembly and to inhibit tau's interaction with the dominant brain phosphatase protein phosphatase 2A isoform AB alpha C. P-region-specific mutations also decrease tau aggregation into filaments and decrease tau's process-inducing activity in a cellular transfection model. In contrast, a phosphorylation-mimicking glutamate cluster in the C-region is neutral with regard to these activities. A glutamate cluster in both the P- and C-regions induces the formation of SDS-resistant conformational domains in tau and suppresses tau's interaction with the neural membrane cortex. The results indicate that modifications in the proline-rich region are sufficient to induce the functional deficiencies of tau that have been observed in AD. They suggest that phosphorylation of the proline-rich region has a crucial role in mediating tau-related changes during disease.
authors.affiliation: Department of Neurobiology, IZN, University of Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Eidenmüller
authors.forename: T
authors.initials: T
authors.lastname: Fath
authors.forename: T
authors.initials: T
authors.lastname: Maas
authors.forename: M
authors.initials: M
authors.lastname: Pool
authors.forename: E
authors.initials: E
authors.lastname: Sontag
authors.forename: R
authors.initials: R
authors.lastname: Brandt
mesh_terms: D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D022101:Microtubule-Organizing Center / Q000502:physiology*; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011392:Proline / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D054648:Protein Phosphatase 2; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D016875:tau Proteins; D018698:Glutamic Acid; D011392:Proline; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2