Annexins A2 and A6 interact with the extreme N terminus of tau and thereby contribute to tau's axonal localization

Abstract

During neuronal development, the microtubule-associated protein tau becomes enriched in the axon, where it remains concentrated in the healthy brain. In tauopathies such as Alzheimer's disease, tau redistributes from the axon to the somatodendritic compartment. However, the cellular mechanism that regulates tau's localization remains unclear. We report here that tau interacts with the Ca-regulated plasma membrane-binding protein annexin A2 (AnxA2) via tau's extreme N terminus encoded by the first exon (E1). Bioinformatics analysis identified two conserved eight-amino-acids-long motifs within E1 in mammals. Using a heterologous yeast system, we found that disease-related mutations and pseudophosphorylation of Tyr-18, located within E1 but outside of the two conserved regions, do not influence tau's interaction with AnxA2. We further observed that tau interacts with the core domain of AnxA2 in a Ca-induced open conformation and interacts also with AnxA6. Moreover, lack of E1 moderately increased tau's association rate to microtubules, consistent with the supposition that the presence of the tau-annexin interaction reduces the availability of tau to interact with microtubules. Of note, intracellular competition through overexpression of E1-containing constructs reduced tau's axonal enrichment in primary neurons. Our results suggest that the E1-mediated tau-annexin interaction contributes to the enrichment of tau in the axon and is involved in its redistribution in pathological conditions.

Mechanisms of secretion and spreading of pathological tau protein

“…Similar short α-helices are also formed upon tau binding to microtubules [179], indicating that context-dependent folding of tau may take place with several interaction partners. Tau interaction with PM may also be partially mediated by interaction of tau N-terminus to PM-located proteins, such as annexin A2 and annexin A6 [180]. While membrane localization, deformation and membrane-dependent folding (and secretion) of tau could be important for the pathological forms of tau, it remains unclear if the lipid and membrane interactions play a role in physiological functions of tau in healthy cells.…”

Tau filaments in neurodegenerative diseases

“…of Tau and annexins may help to explain the axonal localization of tau [13]. Exon 1 contains a primate-specific sequence between residues 18 and 28 of human Tau that has been proposed to mediate interactions with neuronal proteins [14].…”

Microtubule-Dependent Trafficking of Alphaherpesviruses in the Nervous System: The Ins and Outs

“…Its role in uninfected cells is unclear but it has been implicated in axonal guidance, axonal regeneration, and vesicular trafficking [56]. Annexin A2 is a calcium-modulated phospholipid binding protein that regulates lipid raft organization at sites where the plasma membrane contacts the actin cytoskeleton [57], and it also influences the axonal localization of tau [58]. Translational upregulation of Annexin A2 could therefore play a role in remodeling of cortical actin during viral entry into the cytoplasm or could modulate the stability of axonal MTs in preparation for retrograde traffic.…”