title: The frontotemporal dementia mutation R406W blocks tau's interaction with the membrane in an annexin A2-dependent manner.
abstract: Changes of the microtubule-associated protein tau are central in Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). However, the functional consequence of the FTDP-17 tau mutation R406W, which causes a tauopathy clinically resembling AD, is not well understood. We find that the R406W mutation does not affect microtubule interaction but abolishes tau's membrane binding. Loss of binding is associated with decreased trapping at the tip of neurites and increased length fluctuations during process growth. Tandem affinity purification tag purification and mass spectrometry identify the calcium-regulated plasma membrane-binding protein annexin A2 (AnxA2) as a potential interaction partner of tau. Consistently, wild-type tau but not R406W tau interacts with AnxA2 in a heterologous yeast expression system. Sequestration of Ca(2+) or knockdown of AnxA2 abolishes the differential trapping of wild-type and R406W tau. We suggest that the pathological effect of the R406W mutation is caused by impaired membrane binding, which involves a functional interaction with AnxA2 as a membrane-cytoskeleton linker.
authors.affiliation: Department of Neurobiology, University of Osnabrück, Osnabrück, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gauthier-Kemper
authors.forename: Carina
authors.initials: C
authors.lastname: Weissmann
authors.forename: Nataliya
authors.initials: N
authors.lastname: Golovyashkina
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Sebö-Lemke
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.forename: Volker
authors.initials: V
authors.lastname: Gerke
authors.forename: Jürgen J
authors.initials: JJ
authors.lastname: Heinisch
authors.forename: Roland
authors.initials: R
authors.lastname: Brandt
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D017306:Annexin A2 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D008969:Molecular Sequence Data; D016501:Neurites / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology
chemical_list: D017306:Annexin A2; C054369:MAPT protein, human; D016875:tau Proteins