lHeim_B

Tau4A 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	Tau4A	PO4	-2.968	receptor_Tau4A_14	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707	THR-703
2	Tau4A	PO4	-2.619	receptor_Tau4A_3	LYS-692 LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
3	Tau4A	PO4	-2.614	receptor_Tau4A_14	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707	THR-703
4	Tau4A	PO4	-2.466	receptor_Tau4A_14	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707	THR-703
5	Tau4A	PO4	-2.525	receptor_Tau4A_14	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707	THR-703
6	Tau4A	PO4	-2.443	receptor_Tau4A_16	GLU-220 ASP-221 ARG-222 ASP-223 VAL-224
7	Tau4A	PO4	-2.37	receptor_Tau4A_14	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707	THR-703
8	Tau4A	PO4	-2.356	receptor_Tau4A_8	HIS-724 LEU-725 SER-726 ASN-727 VAL-728	SER-726
9	Tau4A	PO4	-2.27	receptor_Tau4A_13	LYS-692 LEU-693 THR-694 PHE-695 ARG-696 GLU-697	THR-694