lHeim_B

Tau9D phosphorylation.

AI Overview (Google's Gemini, March 26, 2026)

Yes, multiple phosphate (PO4) molecules can bind within the same functional regions or "pockets" of the tau protein, particularly in cases of hyperphosphorylation associated with Alzheimer’s disease.

Clustered Phosphorylation Sites: Tau is an intrinsically disordered protein (IDP) with about 85 potential phosphorylation sites. These sites are heavily clustered in the proline-rich region (residues 172-251) and the C-terminal tail (residues 368-441), which flank the microtubule-binding repeats. This high density means multiple phosphate groups often populate these regions simultaneously.
Binding Pocket Overlap: In the pathological, "hyperphosphorylated" state, the balance of kinases and phosphatases is disrupted, leading to the accumulation of many phosphate groups on a single tau molecule.
Specific Examples: Research shows that in Alzheimer’s diseased brains, hyperphosphorylated tau often has 5–9 phosphorylation sites modified, compared to only 2–3 in healthy adults.
Effect of Multiple Phosphates: The binding of multiple phosphates acts cumulatively. As more phosphate groups bind to tau, they remove the positive charge of the microtubule-binding region (MTBR), causing the tau protein to lose its affinity for microtubules, leading to aggregation.
Cooperative Binding: Phosphorylation at one site can sometimes prime or enhance phosphorylation at nearby sites within the same binding domain, facilitating the clustering of multiple phosphates.

In summary, the high concentration of potential sites in specific domains makes it likely that multiple phosphate groups reside in the same or closely positioned areas, directly causing the conformational changes that lead to pathology.

Order of binding	Receptor	Ligand	Affinity	Pocket ID	Residues that formed the binding pocket	Presence of SER, THR, TYR
1	Tau9D	PO4	-2.791	receptor_Tau9D_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
2	Tau9D	PO4	-2.555	receptor_Tau9D_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
3	Tau9D	PO4	-2.299	receptor_Tau9D_1	THR-694 PHE-695 ASN-698 ALA-699	THR-694
4	Tau9D	PO4	-2.384	receptor_Tau9D_1	THR-694 PHE-695 ASN-698 ALA-699	THR-694
5	Tau9D	PO4	-2.195	receptor_Tau9D_8	MET-567 PRO-568 ASP-569 LEU-570 LYS-571
6	Tau9D	PO4	-2.112	receptor_Tau9D_11	THR-537 ARG-538 GLU-539 LYS-541 VAL-543	THR-537
7	Tau9D	PO4	-2.178	receptor_Tau9D_11	THR-537 ARG-538 GLU-539 LYS-541 VAL-543	THR-537
8	Tau9D	PO4	-2.13	receptor_Tau9D_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
9	Tau9D	PO4	-2.097	receptor_Tau9D_13	GLN-586 PRO-587 GLY-588 GLY-590 LYS-591