lHeim_B

Tau21B 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	Tau21B	PO4	-3.195	receptor_Tau21B_3	VAL-604 GLN-605 SER-606 LYS-607 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
2	Tau21B	PO4	-2.715	receptor_Tau21B_4	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707	THR-703
3	Tau21B	PO4	-2.701	receptor_Tau21B_12	VAL-635 THR-636 SER-637 CYS-639 GLY-640 SER-641 LEU-642	THR-636 SER-637 SER-641
4	Tau21B	PO4	-2.652	receptor_Tau21B_3	VAL-604 GLN-605 SER-606 LYS-607 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
5	Tau21B	PO4	-2.685	receptor_Tau21B_3	VAL-604 GLN-605 SER-606 LYS-607 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
6	Tau21B	PO4	-2.534	receptor_Tau21B_3	VAL-604 GLN-605 SER-606 LYS-607 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
7	Tau21B	PO4	-2.5	receptor_Tau21B_11	ILE-734 ASP-735 MET-736 VAL-737 ASP-738 SER-739 LEU-742	SER-739
8	Tau21B	PO4	-2.487	receptor_Tau21B_1	ARG-538 GLU-539 PRO-540 LYS-541 VAL-543
9	Tau21B	PO4	-2.484	receptor_Tau21B_4	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707	THR-703