lHeim_B

Tau15E 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	Tau15E	PO4	-3.154	receptor_Tau15E_2	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 LYS-611 ASP-612	SER-606
2	Tau15E	PO4	-2.703	receptor_Tau15E_6	VAL-667 GLN-668 SER-669 ILE-671 GLY-672 LEU-674 ASP-675	SER-669
3	Tau15E	PO4	-2.532	receptor_Tau15E_8	LYS-692 LEU-693 THR-694 PHE-695 ASN-698	THR-694
4	Tau15E	PO4	-2.502	receptor_Tau15E_1	VAL-680 PRO-681 GLY-682 GLY-683 GLY-684 ASN-685 LYS-686
5	Tau15E	PO4	-2.431	receptor_Tau15E_14	LYS-692 LEU-693 THR-694 ARG-696 GLU-697 HIS-724 SER-726	THR-694 SER-726
6	Tau15E	PO4	-2.435	receptor_Tau15E_14	LYS-692 LEU-693 THR-694 ARG-696 GLU-697 HIS-724 SER-726	THR-694 SER-726
7	Tau15E	PO4	-2.688	receptor_Tau15E_14	LYS-692 LEU-693 THR-694 ARG-696 GLU-697 HIS-724 SER-726	THR-694 SER-726
8	Tau15E	PO4	-2.877	receptor_Tau15E_14	LYS-692 LEU-693 THR-694 ARG-696 GLU-697 HIS-724 SER-726	THR-694 SER-726
9	Tau15E	PO4	-2.519	receptor_Tau15E_14	LYS-692 LEU-693 THR-694 ARG-696 GLU-697 HIS-724 SER-726	THR-694 SER-726