Loss of stability and unfolding cooperativity in hPGK1 upon
gradual structural perturbation of its N-terminal domain
hydrophobic core

J 2022

Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core

JUAN, Luis Pacheco-Garcia, Dmitry S LOGINOV, Athi N NAGANATHAN, Pavla VANKOVA, Mario CANO-MUNOZ et. al.

Základní údaje

Originální název

Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core

Autoři

JUAN, Luis Pacheco-Garcia, Dmitry S LOGINOV, Athi N NAGANATHAN, Pavla VANKOVA, Mario CANO-MUNOZ, Petr MAN a Angel L PEY

Vydání

Nature Scientific Reports, London, NATURE RESEARCH, 2022, 2045-2322

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10600 1.6 Biological sciences

Stát vydavatele

Německo

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.600

Kód RIV

RIV/00216224:14740/22:00128775

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1038/s41598-022-22088-1

UT WoS

000867889200030

Klíčová slova anglicky

Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Phosphoglycerate Kinase; Protein Denaturation; Protein Folding; Thermodynamics

Štítky

ne MU, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 28. 2. 2023 19:14, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Phosphoglycerate kinase has been a model for the stability, folding cooperativity and catalysis of a two-domain protein. The human isoform 1 (hPGK1) is associated with cancer development and rare genetic diseases that affect several of its features. To investigate how mutations affect hPGK1 folding landscape and interaction networks, we have introduced mutations at a buried site in the N-terminal domain (F25 mutants) that either created cavities (F25L, F25V, F25A), enhanced conformational entropy (F25G) or introduced structural strain (F25W) and evaluated their effects using biophysical experimental and theoretical methods. All F25 mutants folded well, but showed reduced unfolding cooperativity, kinetic stability and altered activation energetics according to the results from thermal and chemical denaturation analyses. These alterations correlated well with the structural perturbation caused by mutations in the N-terminal domain and the destabilization caused in the interdomain interface as revealed by H/D exchange under native conditions. Importantly, experimental and theoretical analyses showed that these effects are significant even when the perturbation is mild and local. Our approach will be useful to establish the molecular basis of hPGK1 genotype-phenotype correlations due to phosphorylation events and single amino acid substitutions associated with disease.

Návaznosti

90127, velká výzkumná infrastruktura

Název: CIISB II

Citovat

JUAN, Luis Pacheco-Garcia, Dmitry S LOGINOV, Athi N NAGANATHAN, Pavla VANKOVA, Mario CANO-MUNOZ, Petr MAN a Angel L PEY. Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core. Nature Scientific Reports. London: NATURE RESEARCH, 2022, roč. 12, č. 1, s. 17200-17216. ISSN 2045-2322. Dostupné z: https://dx.doi.org/10.1038/s41598-022-22088-1.

@article{2262560,
   author = {Juan, Luis PachecoandGarcia and Loginov, Dmitry S and Naganathan, Athi N and Vankova, Pavla and CanoandMunoz, Mario and Man, Petr and Pey, Angel L},
   article_location = {London},
   article_number = {1},
   doi = {http://dx.doi.org/10.1038/s41598-022-22088-1},
   keywords = {Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Phosphoglycerate Kinase; Protein Denaturation; Protein Folding; Thermodynamics},
   language = {eng},
   issn = {2045-2322},
   journal = {Nature Scientific Reports},
   title = {Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core},
   url = {https://www.nature.com/articles/s41598-022-22088-1},
   volume = {12},
   year = {2022}
}

TY  - JOUR
ID  - 2262560
AU  - Juan, Luis Pacheco-Garcia - Loginov, Dmitry S - Naganathan, Athi N - Vankova, Pavla - Cano-Munoz, Mario - Man, Petr - Pey, Angel L
PY  - 2022
TI  - Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core
JF  - Nature Scientific Reports
VL  - 12
IS  - 1
SP  - 17200
EP  - 17200
PB  - NATURE RESEARCH
SN  - 20452322
KW  - Humans
KW  - Hydrophobic and Hydrophilic Interactions
KW  - Kinetics
KW  - Phosphoglycerate Kinase
KW  - Protein Denaturation
KW  - Protein Folding
KW  - Thermodynamics
UR  - https://www.nature.com/articles/s41598-022-22088-1
N2  - Phosphoglycerate kinase has been a model for the stability, folding cooperativity and catalysis of a two-domain protein. The human isoform 1 (hPGK1) is associated with cancer development and rare genetic diseases that affect several of its features. To investigate how mutations affect hPGK1 folding landscape and interaction networks, we have introduced mutations at a buried site in the N-terminal domain (F25 mutants) that either created cavities (F25L, F25V, F25A), enhanced conformational entropy (F25G) or introduced structural strain (F25W) and evaluated their effects using biophysical experimental and theoretical methods. All F25 mutants folded well, but showed reduced unfolding cooperativity, kinetic stability and altered activation energetics according to the results from thermal and chemical denaturation analyses. These alterations correlated well with the structural perturbation caused by mutations in the N-terminal domain and the destabilization caused in the interdomain interface as revealed by H/D exchange under native conditions. Importantly, experimental and theoretical analyses showed that these effects are significant even when the perturbation is mild and local. Our approach will be useful to establish the molecular basis of hPGK1 genotype-phenotype correlations due to phosphorylation events and single amino acid substitutions associated with disease.
ER  -

JUAN, Luis Pacheco-Garcia, Dmitry S LOGINOV, Athi N NAGANATHAN, Pavla VANKOVA, Mario CANO-MUNOZ, Petr MAN a Angel L PEY. Loss of stability and unfolding cooperativity in hPGK1 upon gradual structural perturbation of its N-terminal domain hydrophobic core. \textit{Nature Scientific Reports}. London: NATURE RESEARCH, 2022, roč.~12, č.~1, s.~17200-17216. ISSN~2045-2322. Dostupné z: https://dx.doi.org/10.1038/s41598-022-22088-1.

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