Tau and Membranes: Interactions That Promote Folding and Condensation

Abstract

Tau misfolding and assembly is linked to a number of neurodegenerative diseases collectively described as tauopathies, including Alzheimer’s disease (AD) and Parkinson’s disease. Anionic cellular membranes, such as the cytosolic leaflet of the plasma membrane, are sites that concentrate and neutralize tau, primarily due to electrostatic interactions with tau’s microtubule binding repeat domain (RD). In addition to electrostatic interactions with lipids, tau also has interactions with membrane proteins, which are important for tau’s cellular functions. Tau also interacts with lipid tails to facilitate direct translocation across the membrane and can form stable protein-lipid complexes involved in cell-to-cell transport. Concentrated tau monomers at the membrane surface can form reversible condensates, change secondary structures, and induce oligomers, which may eventually undergo irreversible crosslinking and fibril formation. These β-sheet rich tau structures are capable of disrupting membrane organization and are toxic in cell-based assays. Given the evidence for relevant membrane-based tau assembly, we review the emerging hypothesis that polyanionic membranes may serve as a site for phase-separated tau condensation. Membrane-mediated phase separation may have important implications for regulating tau folding/misfolding, and may be a powerful mechanism to spatially direct tau for native membrane-mediated functions.

Unbiased proteomic profiling reveals the IP3R modulator AHCYL1/IRBIT as a novel interactor of microtubule-associated protein tau

“…Among these proteins, we found that recombinant htau40 interacts with a handful of previously described proteins, including DNAJ (heat shock protein 40 kD), S100β, and bridging integrator 1 ( 37 , 38 , 39 , 40 ). Given the high affinity of the intrinsically disordered tau for many biomolecules ( 52 ), it is nevertheless surprising that we could detect only a relatively small number of polypeptides interacting with tau in vitro in our microarray chips. One explanation may be that recombinant proteins spotted on the chip might carry post-translational modifications of insect Sf9 cells, which may influence in vitro –binding features of the candidate polypeptides.…”

Tau forms dynamic hot spots that are resistant to microtubule perturbations and cholesterol depletion

“…The association of Tau with the plasma membrane can occur directly through electrostatic interactions with anionic lipids 15,16 and indirectly through interactions with membrane-associated proteins, such as Fyn 5 , dynactin 17 , and annexin A2 18 . Moreover, Tau interacts with microtubules and actin filaments, anchoring them to the plasma membrane 10 . Despite the critical importance of Tau-membrane interactions, quantifying how Tau behaves and organizes at the plasma membrane in a native cellular environment has previously proven challenging, thereby limiting our understanding of how this protein executes its function in this compartment 11 .…”

“…The association of Tau with the plasma membrane can occur directly through electrostatic interactions with anionic lipids 14,15 and indirectly through interactions with membrane-associated proteins, such as the Src kinase Fyn 16 , the motor protein dynactin 17 , and the phospholipid-binding protein annexin A2 18 . Moreover, Tau interacts with microtubules and actin filaments, anchoring them to the plasma membrane 19 . The question arises whether Tau forms aggregates near the plasma membrane, and if so, how stable these assemblies are.…”

“… ABSTRACT Dysregulation of Tau in Alzheimer’s disease affects multiple cellular compartments and functions 1,2 . Tau interacts directly with and translocates through the plasma membrane 3–7 , a potential site of Tau fibril and membrane pore formation 8–10 , but its physiological state and behavior in this compartment are unknown 11 . Using quantitative single-molecule imaging in live cells, we observed that Tau exhibits both confined and free diffusion near the plasma membrane.…”

Distinct lipid membrane-mediated pathways of Tau assembly revealed by single-molecule analysis

“…Membranes can regulate association and folding of intrinsically disordered proteins (IDPs), and affect aggregation propensities and functions of amyloid proteins. [17][18][19][20] Tau protein has been reported to interact with lipid membranes in vivo, [21][22][23][24] which may enhance its ability to stabilize microtubules and assist the localisation of organelles. For example, the combination of Tau protein with Golgi membranes can serve as a linker between Golgi and microtubules.…”