A class III ligand oscillates between internal and terminal
binding modes as it engages with the Dishevelled PDZ domain

J 2025

A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain

KUMAR, Jitender; Miroslav MICKA; Jan KOMÁREK; Tomáš KLUMPLER; Vojtěch BYSTRÝ et al.

Základní údaje

Originální název

A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain

Autoři

KUMAR, Jitender; Miroslav MICKA; Jan KOMÁREK ; Tomáš KLUMPLER; Vojtěch BYSTRÝ; Remco SPRANGERS; Cyril BARINKA; Vítězslav BRYJA a Konstantinos TRIPSIANES

Vydání

Structure, CAMBRIDGE, CELL PRESS, 2025, 0969-2126

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.300 v roce 2024

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14740/25:00142910

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

MULTIPLE SEQUENCE ALIGNMENT; DYNAMIC ALLOSTERY; STRUCTURAL BASIS; PHAGE DISPLAY; PROTEIN; RECOGNITION; OVEREXPRESSION; PLASTICITY; PROMISCUITY; SPECIFICITY

Štítky

14314010, CF BIC, CF BIOIT, CF GEN, CF PROT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 14. 3. 2026 20:22, Mgr. Eva Dubská

Anotace

V originále

One of the largest domain-motif interactomes in human involves PSD-95/Discs-large/ZO-1 (PDZ) domains. The framework for understanding the PDZ interactome is well established; however the functional dynamics associated with PDZ-ligand interactions are poorly understood. Here, we report a dual PDZ-binding mode that ascribes unique dynamic features to class III ligand recognition. The crystal structure revealed that the PDZ domain can recognize either of the carboxylate moieties (terminal or internal) present in the class III ligand and laid out the register rules responsible for the dual recognition. Variants of the ligand designed to retain one or the other carboxylate of the native sequence were sufficient for PDZ binding. The conformational dynamics of PDZ probed by NMR relaxation dispersion experiments demonstrated that the class III ligand is shuffling binding modes as it engages with the PDZ domain. Our mechanistic findings reveal yet another aspect of PDZ binding plasticity specific to class III ligands.

Návaznosti

EH23_015/0008175, projekt VaV

Název: Inovace České infrastruktury pro integrativní strukturní biologii

GA22-25365S, projekt VaV

Název: Porozumění funkce Dishevelled v jednotlivých buněčných kompartmentech

Investor: Grantová agentura ČR, Porozumění funkce Dishevelled v jednotlivých buněčných kompartmentech

GA23-06913S, projekt VaV

Název: Pochopení vztahu strukturně uspořádaných a neuspořádaných částí proteinu Dishevellled pro jeho funkci v signalizaci Wnt

Investor: Grantová agentura ČR, Pochopení procesů vnitřní uspořádanosti a neuspořádanosti pro funkci proteinu Dishevelled a signalizaci Wnt

101159708, interní kód MU

Název: UpstreaM synergIes to overcome Locked-in effects in widEning regions and broaden internationalization pathwayS for susTainable innOvatioN and compEtitive grant applications

Investor: Evropská unie, UpstreaM synergIes to overcome Locked-in effects in widEning regions and broaden internationalization pathwayS for susTainable innOvatioN and compEtitive grant applications, Rozšiřování účasti a posílení ERA

90242, velká výzkumná infrastruktura

Název: CIISB III

90267, velká výzkumná infrastruktura

Název: NCMG III

Citovat

KUMAR, Jitender; Miroslav MICKA; Jan KOMÁREK; Tomáš KLUMPLER; Vojtěch BYSTRÝ; Remco SPRANGERS; Cyril BARINKA; Vítězslav BRYJA a Konstantinos TRIPSIANES. A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain. Structure. CAMBRIDGE: CELL PRESS, 2025, roč. 33, č. 8, s. 1362-1373. ISSN 0969-2126. Dostupné z: https://doi.org/10.1016/j.str.2025.05.012.

@article{2540720,
   author = {Kumar, Jitender and Micka, Miroslav and Komárek, Jan and Klumpler, Tomáš and Bystrý, Vojtěch and Sprangers, Remco and Barinka, Cyril and Bryja, Vítězslav and Tripsianes, Konstantinos},
   article_location = {CAMBRIDGE},
   article_number = {8},
   doi = {https://doi.org/10.1016/j.str.2025.05.012},
   keywords = {MULTIPLE SEQUENCE ALIGNMENT; DYNAMIC ALLOSTERY; STRUCTURAL BASIS; PHAGE DISPLAY; PROTEIN; RECOGNITION; OVEREXPRESSION; PLASTICITY; PROMISCUITY; SPECIFICITY},
   language = {eng},
   issn = {0969-2126},
   journal = {Structure},
   title = {A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain},
   url = {https://www.sciencedirect.com/science/article/abs/pii/S096921262500190X?via%3Dihub},
   volume = {33},
   year = {2025}
}

TY  - JOUR
ID  - 2540720
AU  - Kumar, Jitender - Micka, Miroslav - Komárek, Jan - Klumpler, Tomáš - Bystrý, Vojtěch - Sprangers, Remco - Barinka, Cyril - Bryja, Vítězslav - Tripsianes, Konstantinos
PY  - 2025
TI  - A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain
JF  - Structure
VL  - 33
IS  - 8
SP  - 1362-1373
EP  - 1362-1373
PB  - CELL PRESS
SN  - 09692126
KW  - MULTIPLE SEQUENCE ALIGNMENT
KW  - DYNAMIC ALLOSTERY
KW  - STRUCTURAL BASIS
KW  - PHAGE DISPLAY
KW  - PROTEIN
KW  - RECOGNITION
KW  - OVEREXPRESSION
KW  - PLASTICITY
KW  - PROMISCUITY
KW  - SPECIFICITY
UR  - https://www.sciencedirect.com/science/article/abs/pii/S096921262500190X?via%3Dihub
N2  - One of the largest domain-motif interactomes in human involves PSD-95/Discs-large/ZO-1 (PDZ) domains. The framework for understanding the PDZ interactome is well established; however the functional dynamics associated with PDZ-ligand interactions are poorly understood. Here, we report a dual PDZ-binding mode that ascribes unique dynamic features to class III ligand recognition. The crystal structure revealed that the PDZ domain can recognize either of the carboxylate moieties (terminal or internal) present in the class III ligand and laid out the register rules responsible for the dual recognition. Variants of the ligand designed to retain one or the other carboxylate of the native sequence were sufficient for PDZ binding. The conformational dynamics of PDZ probed by NMR relaxation dispersion experiments demonstrated that the class III ligand is shuffling binding modes as it engages with the PDZ domain. Our mechanistic findings reveal yet another aspect of PDZ binding plasticity specific to class III ligands.
ER  -

KUMAR, Jitender; Miroslav MICKA; Jan KOMÁREK; Tomáš KLUMPLER; Vojtěch BYSTRÝ; Remco SPRANGERS; Cyril BARINKA; Vítězslav BRYJA a Konstantinos TRIPSIANES. A class III ligand oscillates between internal and terminal binding modes as it engages with the Dishevelled PDZ domain. \textit{Structure}. CAMBRIDGE: CELL PRESS, 2025, roč.~33, č.~8, s.~1362-1373. ISSN~0969-2126. Dostupné z: https://doi.org/10.1016/j.str.2025.05.012.

Přehled o publikaci