lHeim_B

Tau14E 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	Tau14E	PO4	-2.941	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
2	Tau14E	PO4	-2.611	receptor_Tau14E_7	MET-736 VAL-737 ASP-738 SER-739 PRO-740 LEU-742 ALA-743	SER-739
3	Tau14E	PO4	-2.547	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
4	Tau14E	PO4	-2.675	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
5	Tau14E	PO4	-2.895	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
6	Tau14E	PO4	-2.656	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
7	Tau14E	PO4	-2.591	receptor_Tau14E_5	ARG-696 GLU-697 ALA-699 LYS-700 ALA-701 THR-703 ASP-704 HIS-705 ALA-707 ILE-709 TYR-711	THR-703 TYR-711
8	Tau14E	PO4	-2.511	receptor_Tau14E_6	LEU-693 THR-694 PHE-695 ASN-698 ALA-699	THR-694
9	Tau14E	PO4	-2.482	receptor_Tau14E_1	SER-602 ASN-603 VAL-604 GLN-605 SER-606 GLY-609 SER-610 LYS-611 ASP-612	SER-602 SER-606 SER-610