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@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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