lHeim_B

Tau24C 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	Tau24C	PO4	-2.837	receptor_Tau24C_2	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 GLU-708 ILE-709	THR-703
2	Tau24C	PO4	-2.658	receptor_Tau24C_3	LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
3	Tau24C	PO4	-2.254	receptor_Tau24C_3	LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
4	Tau24C	PO4	-2.213	receptor_Tau24C_2	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 GLU-708 ILE-709	THR-703
5	Tau24C	PO4	-2.504	receptor_Tau24C_2	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 GLU-708 ILE-709	THR-703
6	Tau24C	PO4	-2.17	receptor_Tau24C_1	ARG-723 HIS-724 LEU-725
7	Tau24C	PO4	-2.131	receptor_Tau24C_9	GLN-586 PRO-587 GLY-588 GLY-590 LYS-591
8	Tau24C	PO4	-2.012	receptor_Tau24C_2	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 GLU-708 ILE-709	THR-703
9	Tau24C	PO4	-1.941	receptor_Tau24C_6	THR-537 ARG-538 GLU-539 LYS-541	THR-537