The frontotemporal dementia mutation R406W blocks tau’s interaction with the membrane in an annexin A2–dependent manner

Abstract

The R406W mutation prevents tau from functioning as a linker between the membrane and the microtubule cytoskeleton.

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

“…In contrast, human tau overexpression from the GAL1/10 promoter in yeast, which lacks an endogenous tau homolog, does not produce any detectable phenotype in logarithmically growing wild-type cells [23,66]. Yet, it has been reported that co-expression with the gene encoding synuclein aggravates the toxic effects of overexpression of the latter [88].…”

“…All these modifications may affect the interaction with more than 70 predicted tau binding partners [11], including the tyrosine kinase fyn, the membrane-associated protein annexin A2, and its effector protein phosphatase PP2A [66][67][68]. Despite this plethora of regulatory systems and interactions, knockout mice lacking a functional tau gene do not display severe defects in brain function or development [69], which suggests the presence of redundant and compensatory mechanims in vertebrates.…”

“…the E3 ubiquitin ligase Axotropin/MARCH7 [54]. As a complementary strategy, we have expressed tagged versions of wildtype and a mutant tau (R406W) together with annexin A2 in yeast to confirm their interaction by coimmunoprecipitations, thus evading interferences which might be caused by larger neuron-specific protein complexes [66].…”

“…Ser409 in the tau protein was specifically identified as a key residue, whose phosphorylation is crucial to produce the aggregated forms in yeast [77]. Thus, although aggregates of hyperphosphorylated tau do form [78] could be used for studies of effects on tau phosphorylation and aggregation upon co-expression PP2A function in double mutant pph21Δ pph22Δ upon co-expression with tau PIN1 function in ess1Δ upon co-expression with tau [61,79] Use of deletions to study specific modifications of tau use of rim11Δ/mds1Δ to reduce tau phosphorylation and study its aggregation [76] sod2Δ to study oxidative stress [77] and its effect on tau aggregation temperature-sensitive mutants in proteasomal proteases to investigate their effect on tau processing Heterologous gene expression tau for purposes of protein production and biochemical/immunological approaches [77,81] expression of tau and annexin A2 for Co-IPs [66] expression of all three heterologous genes encoding human AMPK subunits [81] to study their effect on tau phosphorylation and aggregation expression of genes for modifying enzymes (e.g. acetyltransferase p300 [55] to study the role of these modifications for tau aggregation Chimeric gene expression expression of tau and human tubulin or a hybrid yeast/human tubulin gene to investigate the interaction with microtubules in yeast Yeast two-hybrid assays (YTH) identification of E3 ubiquitin ligase modifying tau [54] and other new interactors Protein aggregation assays application of colony-colour assay for prion functions to tau aggregation [80] use of fluorescence labels either in conjunction with FACS as demonstrated for Aß [83] or with FRET to study tau aggregation and its interaction with other proteins Synthetic lethal screens use of a platform yeast strain co-expressing the genes for tau and the Aß peptide to screen for suppressors from cDNA libraries or for high-throughput drug screens use of tau overexpression strain to screen for cDNA clones enhancing/provoking toxicity [4] Chronological aging test the effects of tau variants on long-term survival of yeast transformants in synthetic medium [9] to obtain a phenotype useful for genetic screens of the tau interactome [9] Synthetic biology establish entire human modification or signaling pathways in yeast platform strains (lacking the yeast orthologous genes if required and complemented by the human counterparts) to establish a "humanized yeast physiology" * aspects also applicable to the alternative non-conventional yeast K. lactis (but not yet examined for tau-related functions) are underlined.…”

The molecular mechanism of the Tau-Fyn interaction and dendritic targeting in neurons

“…The proline-rich domain of Tau contains 7 PXXP motifs, through which Tau can bind to the SH3 domains of other proteins, such as the Src family tyrosine kinase, Fyn. Tau can also bind to cell membranes by means of its N-terminal region, probably through an interaction with the membrane lipid binding protein, Annexin A2 [10].…”