lHeim_B

Tau4E 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	Tau4E	PO4	-3.12	receptor_Tau4E_13	ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709	THR-703
2	Tau4E	PO4	-2.816	receptor_Tau4E_16	VAL-667 GLN-668 SER-669 GLY-672 SER-673 LEU-674 ASP-675	SER-669 SER-673
3	Tau4E	PO4	-2.454	receptor_Tau4E_13	ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709	THR-703
4	Tau4E	PO4	-2.406	receptor_Tau4E_13	ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709	THR-703
5	Tau4E	PO4	-2.732	receptor_Tau4E_13	ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709	THR-703
6	Tau4E	PO4	-2.359	receptor_Tau4E_16	VAL-667 GLN-668 SER-669 GLY-672 SER-673 LEU-674 ASP-675	SER-669 SER-673
7	Tau4E	PO4	-2.27	receptor_Tau4E_10	MET-567 PRO-568 ASP-569 LEU-570 LYS-571
8	Tau4E	PO4	-2.178	receptor_Tau4E_13	ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709	THR-703
9	Tau4E	PO4	-2.163	receptor_Tau4E_4	GLY-343 GLU-344 ASP-345 THR-346 LYS-347 GLU-348 ALA-349 LYS-465 THR-466 LYS-467 ILE-468	THR-346 THR-466