Comparison of ligand binding and conformational stability of human calmodulin with its homolog from the malaria parasite<i>Plasmodium falciparum</i>

Juhász, Tünde; Kardos, József; Dürvanger, Zsolt; Harmat, V.; Liliom, Károly

doi:10.1096/fba.2020-00013

Cited by 7 publications

(11 citation statements)

References 52 publications

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“…CaM conformations have also been studied by electrophoretic separation in native gels [ 19 , 29 , 30 ] because proteins mobility in an electrical field depends on the electrostatic driving force, the hydrodynamic drag, amino acid composition, charge, shape, mass as well as features of the microenvironment such as pH and viscosity. Importantly, previous evidence indicates that pH gradient can induce changes in CaM [ 33 ] and that the electrophoretic mobility of Ca 2+ -CaM and EGTA-CaM is different in aqueous buffers as it occurred in this work and depends on changes in the molecular conformation [ 34 , 35 , 36 ]. Thus, based in these facts we characterized the conformational changes of Ca 2+ -CaM and EGTA-CaM by 2D electrophoresis in native gels and we found that MEL induced stable modifications on the conformation of Ca 2+ -CaM both in aqueous and lipidic microenvironments.…”

Section: Discussionmentioning

confidence: 63%

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

Argueta

Solís‐Chagoyán

Estrada-Reyes

et al. 2022

IJMS

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Melatonin (MEL) is a pleiotropic indolamine that reaches multiple intracellular targets. Among these, MEL binds to calmodulin (CaM) with high affinity. In presence of Ca2+, CaM binds to CaM-dependent kinase II (CaMKII). The Ca2+-CaM/CaMKII pathway regulates a myriad of brain functions in different cellular compartments. Evidence showing the regulation of this cellular pathway by MEL is scarce. Thus, our main objective was to study the interaction of MEL with CaM and its effects on CaMKII activity in two microenvironments (aqueous and lipidic) naturally occurring within the cell. In addition, colocalization of MEL with CaM in vivo was explored in mice brain hippocampus. In vitro CaM-MEL interaction and the structural conformations of CaM in the presence of this indoleamine were assessed through electrophoretic mobility and isoelectric point. The functional consequence of this interaction was evaluated by measuring CaMKII activity. Ca2+-CaM-MEL increased the activity of CaMKII in aqueous buffer but reduced the kinase activity in lipid buffer. Importantly, MEL colocalizes in vivo with Ca2+-CaM in the hippocampus. Our evidence suggests that MEL regulates the key cellular Ca2+-CaM/CaMKII pathway and might explain why physiological MEL concentrations reduce CaMKII activity in some experimental conditions, while in others it drives biological processes through activation of this kinase.

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Section: Discussionmentioning

confidence: 63%

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

Argueta

Solís‐Chagoyán

Estrada-Reyes

et al. 2022

IJMS

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“…The estimated K ds are in the nM order, with the following affinity order: BIM-VII > BIM-XI > BIM-IV > BIM-X > BIM-II > CPZ ( Table 1 ); which makes this series of compounds desirable to be considered as possible anti-CaM drugs. Many of the inhibitors reported so far are in the micromolar range, such as KAR-2 (5 mM) [ 28 ], Imipramine (14 mM) [ 29 ], Serotonin (0.71 mM), Chlorpromazine (0.97 mM) [ 26 ], Trifluoperazine (1 mM), W7 (7 mM) [ 30 ] and Lubeluzole (2.9 mM) [ 31 ]; only some peptides are in the nanomolar range [ 32 ]. The stoichiometry of the compounds is from the ratio of 1:2 to 1:4, which is mainly attributed to the size of each compound.…”

Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimides New Ligands of CaM Protein

et al. 2022

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In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from Staurosporine, an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor hCaM M124C-mBBr) to directly determine binding parameters experimentally (Kd and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a Kd between 193–248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔGExperimental and ΔGTheoretical (r2 = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors.

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“…Las conformaciones de CaM se han caracterizado por medio de su separación electroforética en geles nativos (Chou et al, 2001;Johnson, 2006;Shukla et al, 2016) debido a que la movilidad de las proteínas en un campo eléctrico depende de las fuerzas electrostáticas conductoras en un campo hidrodinámico, así como de la composición de aminoácidos, la carga, la forma, la masa, así como las características del ambiente como la viscosidad. De manera importante se ha descrito que los gradientes de pH pueden inducir cambios en la estructura de la CaM (Atilgan et al, 2011) y que la movilidad electroforética de la Ca 2+ -CaM y de EGTA-CaM es diferente en buffers acuosos como se mostró en este trabajo y que como mencionamos anteriormente dependen de los cambios en la conformación estructural de la CaM (Benítez-King et al, 1991b;Heydorn et al, 1987;Juhász et al, 2020).…”

Section: Discussionunclassified

Interacción calmodulina-melatonina: efectos sobre la oxidación de la calmodulina y la actividad de la calmodulina cinasa II

Donohué

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Reactive oxygen species are the most reactive molecules that, among other characteristics, have different half-lives, cellular concentrations, and reaction targets. They are present in different compartments and react with different gradients of molecules in the cell. In particular, proteins can react with almost all oxygen radicals present in the cell, and ultimately, these oxidation reactions produce conformational changes in these molecules due to carbonylation and sulfoxidation that impact different cellular functions. In the case of calmodulin, a protein that acts as a Ca 2+ sensor, it can be oxidized by oxygen free radicals and can undergo modifications in its secondary structure, and consequently, its function can be altered until it is degraded. viii 12. Referencias .

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Comparison of ligand binding and conformational stability of human calmodulin with its homolog from the malaria parasitePlasmodium falciparum

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 7 publications

References 52 publications

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

Further Evidence of the Melatonin Calmodulin Interaction: Effect on CaMKII Activity

Bisindolylmaleimides New Ligands of CaM Protein

Interacción calmodulina-melatonina: efectos sobre la oxidación de la calmodulina y la actividad de la calmodulina cinasa II

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