Tau23C phosphorylation.      Download


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	Tau23C	PO4	-2.725	receptor_Tau23C_6	LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
2	Tau23C	PO4	-2.276	receptor_Tau23C_4	MET-567 PRO-568 ASP-569 LEU-570 LYS-571
3	Tau23C	PO4	-2.153	receptor_Tau23C_10	GLU-220 ASP-221 ARG-222 ASP-223
4	Tau23C	PO4	-2.139	receptor_Tau23C_10	GLU-220 ASP-221 ARG-222 ASP-223
5	Tau23C	PO4	-2.249	receptor_Tau23C_10	GLU-220 ASP-221 ARG-222 ASP-223
6	Tau23C	PO4	-2.098	receptor_Tau23C_3	GLU-7 PHE-8 GLU-9
7	Tau23C	PO4	-2.053	receptor_Tau23C_6	LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
8	Tau23C	PO4	-2.038	receptor_Tau23C_14	GLY-718 ASP-719 THR-720 SER-721	THR-720 SER-721
9	Tau23C	PO4	-1.883	receptor_Tau23C_3	GLU-7 PHE-8 GLU-9