lHeim_B

Tau9C 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	Tau9C	PO4	-3.003	receptor_Tau9C_4	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
2	Tau9C	PO4	-2.848	receptor_Tau9C_8	VAL-667 GLN-668 SER-669 ILE-671 GLY-672 LEU-674 ASP-675	SER-669
3	Tau9C	PO4	-2.673	receptor_Tau9C_3	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707	THR-703
4	Tau9C	PO4	-2.663	receptor_Tau9C_3	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707	THR-703
5	Tau9C	PO4	-2.476	receptor_Tau9C_2	LYS-692 LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
6	Tau9C	PO4	-2.415	receptor_Tau9C_6	LYS-660 LEU-661 ASP-662 PHE-663 ARG-666 VAL-667
7	Tau9C	PO4	-2.222	receptor_Tau9C_4	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
8	Tau9C	PO4	-2.435	receptor_Tau9C_4	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
9	Tau9C	PO4	-2.506	receptor_Tau9C_4	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610