complex(a(GO:microtubule), p(HGNC:MAPT))
In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding PubMed:21882945
Hsp90 was also shown to increase association of tau with microtubules [114]; however, its binding is not well characterized and it is not known whether this is a direct or indirect process PubMed:21882945
Finally, the FKBP51–Hsp90 complex has been proposed to be responsible for the interaction of tau with phosphatases, helping to restore binding to microtubules [137]. PubMed:21882945
Hsp70 has been shown to both stabilize binding of tau to microtubules [114] and promote its degradation in combination with CHIP [115,116] PubMed:21882945
Recently, the co-chaperone FK506-binding protein 51 kDa (FKBP51) has been implicated as a modulator of tau binding to microtubules PubMed:21882945
Phosphorylation of tau by the kinases GSK3b, Cdk5 and MARK2 is a major regulator of its microtubule interactions PubMed:21882945
In general, phosphorylation of tau reduces its affinity for microtubules [30], while dephosphorylation via enzymes such as PP2A and PP5 restores binding PubMed:21882945
In addition, recent work has demonstrated that Hsc70, the constitutive cytosolic form of Hsp70s, also dynamically regulates the association of tau with microtubules PubMed:21882945
However, under potentially proteotoxic conditions, the post-translational modifications or mutations that damage tau’s affinity for microtubules and favor its aggregation are thought to generate a molecular ‘danger signal’ that specifically alerts the quality control system [112,113]. PubMed:21882945
Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673
Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673
However, when tau becomes hyperphosphorylated, it detaches from microtubules and aggregates, resulting in depolymerization of microtubules and formation of insoluble tau deposits [40] PubMed:29758300
Genetic interaction studies involving ptl-1 and mutants in other genes associated with microtubules such as mec-12 (a-tubulin) and mec-7 (btubulin), suggested a larger functional role of PTL-1 in mechanosensation (45). PubMed:29191965
In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103
This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation PubMed:26631930
In adult neurons, tau mainly distributes into axons, where it interacts with microtubules through the repeat-domain and flanking regions. PubMed:26631930
Hyperphosphorylation of tau at the repeat domain reduces its microtubule binding, which may cause microtubule disassembly, leading to axonal transport deficits. PubMed:26631930
The nitration of these Tyr residues alters the conformation of tau, reduces its binding to microtubules and, depending on the nitration sites, can promote or inhibit aggregation PubMed:26631930
In addition, glycation of tau may reduce the binding of tau to microtubules PubMed:26631930
The nitration of these Tyr residues alters the conformation of tau, reduces its binding to microtubules and, depending on the nitration sites, can promote or inhibit aggregation PubMed:26631930
The nitration of these Tyr residues alters the conformation of tau, reduces its binding to microtubules and, depending on the nitration sites, can promote or inhibit aggregation PubMed:26631930
Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930
In addition, phosphorylation of Ser214 and Thr231 in the flanking region of tau can trigger the detachment of tau from microtubules, whereas phosphorylation at other Thr-Pro or Ser-Pro motifs in the flanking region has only a weak influence on tau–microtubule binding PubMed:26631930
For example,the phosphorylation of KXGS motifs (particularly Ser262) in the repeat domain of tau by MARK, PKA or CaMKII can reduce the affinity of tau to microtubules PubMed:26631930
Interestingly, the PSP-associated tau mutation A152T is localized far away from the repeat domain but still decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
Tau protein with mutations in or near the microtubule-binding domain (for instance, G272V, N279K, ΔK280, P301L, V337M or R406W) tend to have a reduced affinity for microtubules and an increased tendency for aggregation PubMed:26631930
In the pathological case of Alzheimer’s disease (AD) tau becomes hyperphosphorylated, detaches from the microtubules, misfolds, and mislocalizes to the somatodendritic compartment where it aggregates into neurofibrillary tangles. PubMed:25374103
Tau thereby stabilizes microtubules, promotes microtubule assembly and, in particular, regulates the dynamic instability of microtubules that allows reorganization of the cytoskeleton. PubMed:26631930
Tau thereby stabilizes microtubules, promotes microtubule assembly and, in particular, regulates the dynamic instability of microtubules that allows reorganization of the cytoskeleton. PubMed:26631930
This suggests that the stabilization of the microtubule-bound conformation of tau may delay tau aggregation PubMed:26631930
Thus, it is possible that unknown cofactors trigger tau aggregation in the AD brain, whereas phosphorylation may accelerate aggregation indirectly: for example, by detaching tau from microtubules PubMed:26631930
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.