lHeim_B

Tau12D 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	Tau12D	PO4	-2.891	receptor_Tau12D_11	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
2	Tau12D	PO4	-2.707	receptor_Tau12D_4	VAL-604 GLN-605 SER-606 GLY-609 LYS-611 ASP-612	SER-606
3	Tau12D	PO4	-2.525	receptor_Tau12D_6	PRO-681 GLY-682 GLY-683 GLY-684 ASN-685
4	Tau12D	PO4	-2.473	receptor_Tau12D_11	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
5	Tau12D	PO4	-2.686	receptor_Tau12D_11	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
6	Tau12D	PO4	-2.41	receptor_Tau12D_11	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
7	Tau12D	PO4	-2.644	receptor_Tau12D_11	LYS-700 ALA-701 THR-703 ASP-704 HIS-705 GLY-706 ALA-707 ILE-709	THR-703
8	Tau12D	PO4	-2.364	receptor_Tau12D_4	VAL-604 GLN-605 SER-606 GLY-609 LYS-611 ASP-612	SER-606
9	Tau12D	PO4	-2.28	receptor_Tau12D_13	VAL-573 LYS-574 SER-575 GLY-578 THR-580 GLU-581	SER-575 THR-580