lHeim_B

Tau21D 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	Tau21D	PO4	-3.088	receptor_Tau21D_7	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 LYS-611 ASP-612	SER-606
2	Tau21D	PO4	-2.923	receptor_Tau21D_8	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
3	Tau21D	PO4	-2.714	receptor_Tau21D_8	ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
4	Tau21D	PO4	-2.472	receptor_Tau21D_10	PHE-695 ARG-696 GLU-697 ALA-699 TYR-711 SER-713	TYR-711 SER-713
5	Tau21D	PO4	-2.466	receptor_Tau21D_1	THR-537 ARG-538 GLU-539 PRO-540 LYS-541 VAL-543	THR-537
6	Tau21D	PO4	-2.452	receptor_Tau21D_9	VAL-667 GLN-668 SER-669 GLY-672 LEU-674 ASP-675	SER-669
7	Tau21D	PO4	-2.436	receptor_Tau21D_7	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 LYS-611 ASP-612	SER-606
8	Tau21D	PO4	-2.352	receptor_Tau21D_1	THR-537 ARG-538 GLU-539 PRO-540 LYS-541 VAL-543	THR-537
9	Tau21D	PO4	-2.675	receptor_Tau21D_1	THR-537 ARG-538 GLU-539 PRO-540 LYS-541 VAL-543	THR-537