lHeim_B

Tau15B 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	Tau15B	PO4	-3.181	receptor_Tau15B_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
2	Tau15B	PO4	-2.574	receptor_Tau15B_10	VAL-667 GLN-668 SER-669 ILE-671 GLY-672 LEU-674 ASP-675	SER-669
3	Tau15B	PO4	-2.571	receptor_Tau15B_11	THR-346 LYS-347 GLU-348 ALA-349 ASP-350 ASP-463 GLY-464 LYS-465 THR-466 LYS-467 ILE-468 ALA-469 THR-470	THR-346 THR-466 THR-470
4	Tau15B	PO4	-2.904	receptor_Tau15B_11	THR-346 LYS-347 GLU-348 ALA-349 ASP-350 ASP-463 GLY-464 LYS-465 THR-466 LYS-467 ILE-468 ALA-469 THR-470	THR-346 THR-466 THR-470
5	Tau15B	PO4	-3.102	receptor_Tau15B_11	THR-346 LYS-347 GLU-348 ALA-349 ASP-350 ASP-463 GLY-464 LYS-465 THR-466 LYS-467 ILE-468 ALA-469 THR-470	THR-346 THR-466 THR-470
6	Tau15B	PO4	-2.536	receptor_Tau15B_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
7	Tau15B	PO4	-2.753	receptor_Tau15B_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
8	Tau15B	PO4	-2.534	receptor_Tau15B_9	VAL-604 GLN-605 SER-606 CYS-608 GLY-609 SER-610 LYS-611 ASP-612	SER-606 SER-610
9	Tau15B	PO4	-2.51	receptor_Tau15B_11	THR-346 LYS-347 GLU-348 ALA-349 ASP-350 ASP-463 GLY-464 LYS-465 THR-466 LYS-467 ILE-468 ALA-469 THR-470	THR-346 THR-466 THR-470