In silico study of the impact of the PRKAG2-H401Q mutation on AMPK affinity for AMP and ATP
Resumo
Mutations in the PRKAG2 gene, which encodes the γ2 subunit of AMP-activated protein kinase (AMPK), are linked to a rare cardiomyopathy involving glycogen accumulation, left ventricular hypertrophy, and sudden death. This study investigates a novel His401Gln missense mutation in the PRKAG2 gene and its effects on AMPK γ2 subunit dynamics. Through molecular simulations and free energy analyses, we compared AMP and ATP binding affinities between the wild-type and mutant γ2 subunits. Structural modeling and simulations revealed a significant change in ATP binding at site 3 in the mutant AMPK, suggesting that the His401Gln mutation impacts protein binding behavior. This alteration may contribute to the pathological mechanisms of PRKAG2 cardiomyopathy.Referências
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AHMAD, F. et al. Increased α2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy. Circulation, v. 112, n. 20, p. 3140–3148, 15 nov. 2005.
ALBERNAZ SIQUEIRA, M. H. et al. Sudden death associated with a novel H401Q PRKAG2 mutation. EP Europace, v. 22, n. 8, p. 1278–1278, 1 ago. 2020.
ARAD, M. et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Journal of Clinical Investigation, v. 109, n. 3, p. 357–362, 1 fev. 2002.
BAIRWA, S. C.; PARAJULI, N.; DYCK, J. R. B. The role of AMPK in cardiomyocyte health and survival. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, v. 1862, n. 12, p. 2199–2210, dez. 2016.
DAY, P. et al. Structure of a CBS-domain pair from the regulatory γ1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallographica Section D Biological Crystallography, v. 63, n. 5, p. 587–596, 1 mai 2007.
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GOLLOB, M. H. et al. Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Pre-excitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy. Circulation, v. 104, n. 25, p. 3030–3033, 17 dez. 2001.
KOMURCU-BAYRAK, E. et al. Identification of the pathogenic effects of missense variants causing PRKAG2 cardiomyopathy. Archives of Biochemistry and Biophysics, v. 727, p. 109340, set. 2022.
MAGALHÃES, L. P. D. et al. Complicações Cardíacas em Longo Prazo da Síndrome do PRKAG2. Arquivos Brasileiros de Cardiologia, v. 118, n. 1, p. 106–109, 10 jan. 2022.
STEINBERG, G. R.; HARDIE, D. G. New insights into activation and function of the AMPK. Nature Reviews Molecular Cell Biology, v. 24, n. 4, p. 255–272, abr. 2023.
XIAO, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature, v. 449, n. 7161, p. 496–500, set. 2007.
AHMAD, F. et al. Increased α2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy. Circulation, v. 112, n. 20, p. 3140–3148, 15 nov. 2005.
ALBERNAZ SIQUEIRA, M. H. et al. Sudden death associated with a novel H401Q PRKAG2 mutation. EP Europace, v. 22, n. 8, p. 1278–1278, 1 ago. 2020.
ARAD, M. et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. Journal of Clinical Investigation, v. 109, n. 3, p. 357–362, 1 fev. 2002.
BAIRWA, S. C.; PARAJULI, N.; DYCK, J. R. B. The role of AMPK in cardiomyocyte health and survival. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, v. 1862, n. 12, p. 2199–2210, dez. 2016.
DAY, P. et al. Structure of a CBS-domain pair from the regulatory γ1 subunit of human AMPK in complex with AMP and ZMP. Acta Crystallographica Section D Biological Crystallography, v. 63, n. 5, p. 587–596, 1 mai 2007.
DE A. FILHO, J. L.; DEL REAL TAMARIZ, A.; FERNANDEZ, J. H. AutoModel: A Client-Server Tool for Intuitive and Interactive Homology Modeling of Protein-Ligand Complexes. Em: ALVES, R. (Ed.). Advances in Bioinformatics and Computational Biology. Lecture Notes in Computer Science. Cham: Springer International Publishing, 2018. v. 11228p. 78–89.
GOLLOB, M. H. et al. Novel PRKAG2 Mutation Responsible for the Genetic Syndrome of Ventricular Pre-excitation and Conduction System Disease With Childhood Onset and Absence of Cardiac Hypertrophy. Circulation, v. 104, n. 25, p. 3030–3033, 17 dez. 2001.
KOMURCU-BAYRAK, E. et al. Identification of the pathogenic effects of missense variants causing PRKAG2 cardiomyopathy. Archives of Biochemistry and Biophysics, v. 727, p. 109340, set. 2022.
MAGALHÃES, L. P. D. et al. Complicações Cardíacas em Longo Prazo da Síndrome do PRKAG2. Arquivos Brasileiros de Cardiologia, v. 118, n. 1, p. 106–109, 10 jan. 2022.
STEINBERG, G. R.; HARDIE, D. G. New insights into activation and function of the AMPK. Nature Reviews Molecular Cell Biology, v. 24, n. 4, p. 255–272, abr. 2023.
XIAO, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature, v. 449, n. 7161, p. 496–500, set. 2007.
Publicado
02/12/2024
Como Citar
SOUZA, Karine Terra de; DIAS, Glauber Monteiro; FERNANDEZ, Jorge Hernandez.
In silico study of the impact of the PRKAG2-H401Q mutation on AMPK affinity for AMP and ATP. In: SIMPÓSIO BRASILEIRO DE BIOINFORMÁTICA (BSB), 17. , 2024, Vitória/ES.
Anais [...].
Porto Alegre: Sociedade Brasileira de Computação,
2024
.
p. 235-240.
ISSN 2316-1248.
DOI: https://doi.org/10.5753/bsb.2024.245548.
