lHeim_B

Tau12A 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	Tau12A	PO4	-3.028	receptor_Tau12A_5	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
2	Tau12A	PO4	-2.927	receptor_Tau12A_6	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
3	Tau12A	PO4	-2.545	receptor_Tau12A_5	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
4	Tau12A	PO4	-2.495	receptor_Tau12A_5	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
5	Tau12A	PO4	-2.317	receptor_Tau12A_8	LYS-664 VAL-667 GLN-668 SER-669 GLY-672 LEU-674 ASP-675	SER-669
6	Tau12A	PO4	-2.243	receptor_Tau12A_2	VAL-716 GLY-718 ASP-719 THR-720 SER-721	THR-720 SER-721
7	Tau12A	PO4	-2.319	receptor_Tau12A_2	VAL-716 GLY-718 ASP-719 THR-720 SER-721	THR-720 SER-721
8	Tau12A	PO4	-2.231	receptor_Tau12A_6	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
9	Tau12A	PO4	-2.438	receptor_Tau12A_6	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610