The Evolution of Tau Phosphorylation and Interactions

Abstract

Tau is a neuronal microtubule-associated protein (MAP) that is involved in the regulation of axonal microtubule assembly. However, as a protein with intrinsically disordered regions (IDRs), tau also interacts with many other partners in addition to microtubules. Phosphorylation at selected sites modulates tau’s various intracellular interactions and regulates the properties of IDRs. In Alzheimer’s disease (AD) and other tauopathies, tau exhibits pathologically increased phosphorylation (hyperphosphorylation) at selected sites and aggregates into neurofibrillary tangles (NFTs). By bioinformatics means, we tested the hypothesis that the sequence of tau has changed during the vertebrate evolution in a way that novel interactions developed and also the phosphorylation pattern was affected, which made tau prone to the development of tauopathies. We report that distinct regions of tau show functional specialization in their molecular interactions. We found that tau’s amino-terminal region, which is involved in biological processes related to “membrane organization” and “regulation of apoptosis,” exhibited a strong evolutionary increase in protein disorder providing the basis for the development of novel interactions. We observed that the predicted phosphorylation sites have changed during evolution in a region-specific manner, and in some cases the overall number of phosphorylation sites increased owing to the formation of clusters of phosphorylatable residues. In contrast, disease-specific hyperphosphorylated sites remained highly conserved. The data indicate that novel, non-microtubule related tau interactions developed during evolution and suggest that the biological processes, which are mediated by these interactions, are of pathological relevance. Furthermore, the data indicate that predicted phosphorylation sites in some regions of tau, including a cluster of phosphorylatable residues in the alternatively spliced exon 2, have changed during evolution. In view of the “antagonistic pleiotropy hypothesis” it may be worth to take disease-associated phosphosites with low evolutionary conservation as relevant biomarkers into consideration.

Age dependent trans-cellular propagation of human tau aggregates in Drosophila disease models

“…However, in its pathogenic form, tau phosphorylation is enhanced, subsequently deteriorating its biological activity, namely stabilization and assembly of microtubules [27,28]. Consequently, tau detaches itself from the microtubules and tends to aggregate as NFTs [29].…”

Tau: A Signaling Hub Protein

“…Indeed, intrinsically disordered proteins, including tau, are known for their unique structural plasticity, conformational adaptability, and binding promiscuity enabling their involvement in diverse signaling roles (Uversky, 2015 ; Brandt et al, 2020 ). Interestingly, there is a clear evolutionary increase in disorder within the amino-terminal region of tau that likely enabled the development of novel protein-protein interactions (Trushina et al, 2019 ). It is noteworthy that, despite being categorized as an intrinsically disordered protein, tau is known to adopt specific folded conformations as a soluble protein (e.g., global hairpin folding; Jeganathan et al, 2006 ) and in the context of pathology (as identified by conformation-specific antibodies such as Alz50 or MC1; Wolozin et al, 1986 ; Carmel et al, 1996 ; Jicha et al, 1997 , 1999 ).…”

Methylation as a key regulator of Tau aggregation and neuronal health in Alzheimer’s disease

“…Phosphorylation is required for Tau’s association with microtubules. However, hyperphosphorylation of Tau results in its dissociation from microtubules and leads to aggregation [ 10 – 12 ]. The phosphorylated state of Tau, in turn depends on the level of kinase activity and the balance between kinases and phosphatases in neurons [ 13 ].…”