Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14310%2F23%3A00131225" target="_blank" >RIV/00216224:14310/23:00131225 - isvavai.cz</a>
Result on the web
<a href="https://pubs.acs.org/doi/10.1021/acs.biochem.2c00717" target="_blank" >https://pubs.acs.org/doi/10.1021/acs.biochem.2c00717</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acs.biochem.2c00717" target="_blank" >10.1021/acs.biochem.2c00717</a>
Alternative languages
Result language
angličtina
Original language name
Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region
Original language 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2023
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochemistry
ISSN
0006-2960
e-ISSN
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Volume of the periodical
62
Issue of the periodical within the volume
11
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
1631-1642
UT code for WoS article
001008506700001
EID of the result in the Scopus database
2-s2.0-85160628740