J 2023

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

LASORSA, Alessia, Krishnendu BERA, Idir MALKI, Elian DUPRE, Francois-Xavier CANTRELLE et. al.

Basic information

Original name

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

Authors

LASORSA, Alessia, Krishnendu BERA (356 India, belonging to the institution), Idir MALKI, Elian DUPRE, Francois-Xavier CANTRELLE, Hamida MERZOUGUI, Davy SINNAEVE, Xavier HANOULLE, Jozef HRITZ (703 Slovakia, guarantor, belonging to the institution) and Isabelle LANDRIEU

Edition

Biochemistry, Washington, American Chemical Society, 2023, 0006-2960

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10608 Biochemistry and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 2.900 in 2022

RIV identification code

RIV/00216224:14310/23:00131225

Organization unit

Faculty of Science

DOI

UT WoS

001008506700001

Keywords in English

Genes; Molecular dynamics; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Peptides

Tags

Tags

International impact, Reviewed
Změněno: 3/3/2024 23:59, Mgr. Eva Dubská

Abstract

V originále

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.

Links

GF20-05789L, research and development project
Name: Charakterizace přirozeně neuspořádaných proteinů
Investor: Czech Science Foundation, Partner Agency (Austria)
LM2018140, research and development project
Name: e-Infrastruktura CZ (Acronym: e-INFRA CZ)
Investor: Ministry of Education, Youth and Sports of the CR
LTAUSA18168, research and development project
Name: Selektivní NMR značení jako nástroj pro charakterizaci proteinových komplexů zapojených do neurodegenerativních onemocnění
Investor: Ministry of Education, Youth and Sports of the CR, Selective NMR labelling as a tool for characterization of protein complexes involved in neurodegenerative diseases., INTER-ACTION