Publication details
Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region
| Authors | |
|---|---|
| Year of publication | 2023 |
| Type | Article in Periodical |
| Magazine / Source | Biochemistry |
| MU Faculty or unit | |
| Citation | |
| web | https://pubs.acs.org/doi/10.1021/acs.biochem.2c00717 |
| Doi | http://dx.doi.org/10.1021/acs.biochem.2c00717 |
| Keywords | Genes; Molecular dynamics; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Peptides |
| Description | An increase in phosphorylation of the Tau protein isassociatedwith Alzheimer's disease (AD) progression through unclear molecularmechanisms. In general, phosphorylation modifies the interaction ofintrinsically disordered proteins, such as Tau, with other proteins;however, elucidating the structural basis of this regulation mechanismremains challenging. The bridging integrator-1 gene is an AD geneticdeterminant whose gene product, BIN1, directly interacts with Tau.The proline-rich motif recognized within a Tau(210-240) peptideby the SH3 domain of BIN1 (BIN1 SH3) is defined as 216PTPP219, and this interaction is modulated by phosphorylation.Phosphorylation of T217 within the Tau(210-240) peptide ledto a 6-fold reduction in the affinity, while single phosphorylationat either T212, T231, or S235 had no effect on the interaction. Nonetheless,combined phosphorylation of T231 and S235 led to a 3-fold reductionin the affinity, although these phosphorylations are not within theBIN1 SH3-bound region of the Tau peptide. Using nuclear magnetic resonance(NMR) spectroscopy, these phosphorylations were shown to affect thelocal secondary structure and dynamics of the Tau(210-240)peptide. Models of the (un)-phosphorylated peptides were obtained frommolecular dynamics (MD) simulation validated by experimental dataand showed compaction of the phosphorylated peptide due to increasedsalt bridge formation. This dynamic folding might indirectly impactthe BIN1 SH3 binding by a decreased accessibility of the binding site.Regulation of the binding might thus not only be due to local electrostaticor steric effects from phosphorylation but also to the modificationof the conformational properties of Tau. |
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