COEVOLUTION AND CHARACTERIZATION OF MUTANT VOLTAGE-DEPENDENT SODIUM CHANNELS

Millena Ferreira Fernandes; Lucas Bleicher; Artur Santos Miranda

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Paper Title

COEVOLUTION AND CHARACTERIZATION OF MUTANT VOLTAGE-DEPENDENT SODIUM CHANNELS

Authors

Millena Ferreira Fernandes
Lucas Bleicher
Artur Santos Miranda

Modality

Poster

Subject area

Phylogeny and Evolution

Publishing Date

21/11/2024

Country of Publishing

Brazil | Brasil

Language of Publishing

Inglês

Paper Page

https://www.even3.com.br/anais/xmeeting-2024/837611-coevolution-and-characterization-of-mutant-voltage-dependent-sodium-channels

ISBN

978-65-272-0843-3

Keywords

Sodium channels, coevolution, fast inactivation

Summary

Voltage-dependent sodium channels are essential for the generation and propagation of action potentials in excitable cells, including neurons, muscle cells, and cardiac cells. The precise arrangement and amino acid composition of these channels are intrinsically related to their functionalization, so that substitutions or mutations in certain amino acids can lead to the emergence of channelopathies, which, in turn, can alter an individual's heart rhythm. Through the PFstats software, which uses the Residue Coevolution Network Decomposition method, we characterized the main coevolutionary related amino acid residues that play a key role in modulating the inactivation of sodium channels, specifically the alpha subunit type 5 (NaV 1.5), the main variant expressed in mammalian hearts. From coevolution analyses, we used protein sequences to reconstruct the evolutionary history from the perspective of variations found in the IFM motif (Isoleucine-Phenylalanine-Methionine), the main component of fast inactivation of sodium channels. Phylogenetic reconstruction was performed using the functionalities of the MEGA XI software. Additionally, we selected three amino acid residues that coevolve as candidates for evaluating mutant phenotypes of NaV 1.5. Based on PFstats results, nine main amino acid residues that coevolve and interact with the isoleucine of the IFM motif were identified. From the phylogenetic reconstruction performed with NaV 1.5 protein sequences from mammals, reptiles, and birds, we observed that some species have three proteins with important amino acid modifications in the channel inactivation gate. Mammals showed conservation in the IFM amino acid triad, while some representatives of reptiles and birds exhibited modification in two amino acids, forming the LFL triad (Leucine-Phenylalanine-Leucine). Evaluating the three-dimensional structure of the two loops formed by the IFM and LFL amino acids, we observed a shortening of the alpha helix that connects the loop formed by the LFL triplet and the fourth transmembrane domain. Through further evolutionary and structural analyses, we aim to better understand the relationship between these structural differences and their impact on the fast inactivation functionality of the sodium channel. Additionally, the evaluation of selected mutants will contribute to establishing a modulatory relationship between coevolving residues and the sodium channel inactivation gate.

Title of the Event: 20º Congresso Brasileiro de Bioinformática: X-Meeting 2024
City of the Event: Salvador
Title of the Proceedings of the event: X-Meeting presentations
Name of the Publisher: Even3
Means of Dissemination: Meio Digital

How to cite

FERNANDES, Millena Ferreira; BLEICHER, Lucas; MIRANDA, Artur Santos. COEVOLUTION AND CHARACTERIZATION OF MUTANT VOLTAGE-DEPENDENT SODIUM CHANNELS.. In: X-Meeting presentations. Anais...Salvador(BA) Hotel Deville Prime, 2024. Available in: https//www.even3.com.br/anais/xmeeting-2024/837611-COEVOLUTION-AND-CHARACTERIZATION-OF-MUTANT-VOLTAGE-DEPENDENT-SODIUM-CHANNELS. Access in: 02/06/2025