Reduced binding of Tau(210-240) to BIN1: Phosphate charges
prefer n-Src/distal loops over RT-Src loops

J 2025

Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops

GAFFOUR, Amina; Michael BAKKER; Krishnendu BERA a Jana PAVLÍKOVÁ PŘECECHTĚLOVÁ

Základní údaje

Originální název

Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops

Autoři

GAFFOUR, Amina; Michael BAKKER; Krishnendu BERA a Jana PAVLÍKOVÁ PŘECECHTĚLOVÁ

Vydání

BIOPHYSICAL JOURNAL, CAMBRIDGE, CELL PRESS, 2025, 0006-3495

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10403 Physical chemistry

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.100 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/25:00143544

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

PHOSPHORYLATION; TAU-PROTEIN

Štítky

14314020, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 27. 1. 2026 11:57, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

Within the disordered tangles of Tau is a proline-rich region, which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with excellent preventative or remediative targets. This work compiles an extensive (>60 mu s) collection of all-atomistic molecular dynamics simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the proline-rich region, benchmarking various force fields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex were analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact toward the distal and n-Src loops instead of residues in the RT-Src loop.

Návaznosti

101087124, interní kód MU

Název: Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe

Investor: Evropská unie, Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe, Rozšiřování účasti a posílení ERA

873127, interní kód MU

Název: Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease (Akronym: InterTAU)

Investor: Evropská unie, Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease, MSCA Marie Skłodowska-Curie Actions (Excellent Science)

90254, velká výzkumná infrastruktura

Název: e-INFRA CZ II

Citovat

GAFFOUR, Amina; Michael BAKKER; Krishnendu BERA a Jana PAVLÍKOVÁ PŘECECHTĚLOVÁ. Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops. BIOPHYSICAL JOURNAL. CAMBRIDGE: CELL PRESS, 2025, roč. 124, č. 21, s. 3800-3810. ISSN 0006-3495. Dostupné z: https://doi.org/10.1016/j.bpj.2025.09.037.

@article{2549504,
   author = {Gaffour, Amina and Bakker, Michael and Bera, Krishnendu and Pavlíková Přecechtělová, Jana},
   article_location = {CAMBRIDGE},
   article_number = {21},
   doi = {https://doi.org/10.1016/j.bpj.2025.09.037},
   keywords = {PHOSPHORYLATION; TAU-PROTEIN},
   language = {eng},
   issn = {0006-3495},
   journal = {BIOPHYSICAL JOURNAL},
   title = {Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops},
   url = {https://www.cell.com/biophysj/abstract/S0006-3495(25)00617-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0006349525006174%3Fshowall%3Dtrue},
   volume = {124},
   year = {2025}
}

TY  - JOUR
ID  - 2549504
AU  - Gaffour, Amina - Bakker, Michael - Bera, Krishnendu - Pavlíková Přecechtělová, Jana
PY  - 2025
TI  - Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops
JF  - BIOPHYSICAL JOURNAL
VL  - 124
IS  - 21
SP  - 3800-3810
EP  - 3800-3810
PB  - CELL PRESS
SN  - 00063495
KW  - PHOSPHORYLATION
KW  - TAU-PROTEIN
UR  - https://www.cell.com/biophysj/abstract/S0006-3495(25)00617-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0006349525006174%3Fshowall%3Dtrue
N2  - Within the disordered tangles of Tau is a proline-rich region, which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with excellent preventative or remediative targets. This work compiles an extensive (>60 mu s) collection of all-atomistic molecular dynamics simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the proline-rich region, benchmarking various force fields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex were analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact toward the distal and n-Src loops instead of residues in the RT-Src loop.
ER  -

GAFFOUR, Amina; Michael BAKKER; Krishnendu BERA a Jana PAVLÍKOVÁ PŘECECHTĚLOVÁ. Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops. \textit{BIOPHYSICAL JOURNAL}. CAMBRIDGE: CELL PRESS, 2025, roč.~124, č.~21, s.~3800-3810. ISSN~0006-3495. Dostupné z: https://doi.org/10.1016/j.bpj.2025.09.037.

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