lHeim_B

Tau25D 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	Tau25D	PO4	-2.755	receptor_Tau25D_8	LYS-692 LEU-693 THR-694 PHE-695 ASN-698	THR-694
2	Tau25D	PO4	-2.748	receptor_Tau25D_1	VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
3	Tau25D	PO4	-2.402	receptor_Tau25D_1	VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
4	Tau25D	PO4	-2.396	receptor_Tau25D_2	LYS-692 LEU-693 THR-694 PHE-695 ARG-696 GLU-697	THR-694
5	Tau25D	PO4	-2.377	receptor_Tau25D_1	VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
6	Tau25D	PO4	-2.464	receptor_Tau25D_1	VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
7	Tau25D	PO4	-2.35	receptor_Tau25D_9	GLN-315 ALA-316 HIS-317 SER-318	SER-318
8	Tau25D	PO4	-2.207	receptor_Tau25D_1	VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
9	Tau25D	PO4	-2.188	receptor_Tau25D_11	ASP-270 PHE-271 LEU-272 SER-273	SER-273