Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Conformation and Affinity Modulations by Multiple Phosphorylation Occurring in the BIN1 SH3 Domain Binding Site of the Tau Protein Proline-Rich Region

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biochemistry

ISSN

0006-2960

e-ISSN

—

Svazek periodika

62

Číslo periodika v rámci svazku

11

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

1631-1642

Kód UT WoS článku

001008506700001

EID výsledku v databázi Scopus

2-s2.0-85160628740