دورية أكاديمية
Experimental and bioinformatic insights into the effects of epileptogenic variants on the function and trafficking of the GABA transporter GAT-1
| العنوان: | Experimental and bioinformatic insights into the effects of epileptogenic variants on the function and trafficking of the GABA transporter GAT-1 |
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| المؤلفون: | Piniella, Dolores, Canseco, Ania, Vidal, Silvia, Xiol, Clara, Díaz de Bustamante, Aránzazu, Martí-Carrera, Itxaso, Armstrong, Judith, Bastolla, Ugo, Zafra Gómez, Francisco |
| المساهمون: | UAM. Departamento de Biología Molecular |
| بيانات النشر: | MDPI |
| سنة النشر: | 2023 |
| المجموعة: | Universidad Autónoma de Madrid (UAM): Biblos-e Archivo |
| مصطلحات موضوعية: | GABA Transporter, Epilepsy, Intracellular Trafficking, 4-Phenylbutyrate, Biología y Biomedicina / Biología |
| الوصف: | In this article, we identified a novel epileptogenic variant (G307R) of the gene SLC6A1, which encodes the GABA transporter GAT-1. Our main goal was to investigate the pathogenic mechanisms of this variant, located near the neurotransmitter permeation pathway, and compare it with other variants located either in the permeation pathway or close to the lipid bilayer. The mutants G307R and A334P, close to the gates of the transporter, could be glycosylated with variable efficiency and reached the membrane, albeit inactive. Mutants located in the center of the permeation pathway (G297R) or close to the lipid bilayer (A128V, G550R) were retained in the endoplasmic reticulum. Applying an Elastic Network Model, to these and to other previously characterized variants, we found that G307R and A334P significantly perturb the structure and dynamics of the intracellular gate, which can explain their reduced activity, while for A228V and G362R, the reduced translocation to the membrane quantitatively accounts for the reduced activity. The addition of a chemical chaperone (4-phenylbutyric acid, PBA), which improves protein folding, increased the activity of GAT-1WT, as well as most of the assayed variants, including G307R, suggesting that PBA might also assist the conformational changes occurring during the alternative access transport cycle |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | International Journal of Molecular Sciences; https://doi.org/10.3390/ijms24020955Test; Gobierno de España. RTI2018-098712-B-100; International Journal of Molecular Sciences 24.2 (2023): 955; 1661-6596 (print); 1422-0067 (online); http://hdl.handle.net/10486/706682Test; 955-1; 955-26; 24 |
| DOI: | 10.3390/ijms24020955 |
| الإتاحة: | https://doi.org/10.3390/ijms24020955Test http://hdl.handle.net/10486/706682Test |
| حقوق: | © 2023 by the authors. Licensee MDPI, Basel, Switzerland ; Reconocimiento ; openAccess |
| رقم الانضمام: | edsbas.1B4D2703 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/ijms24020955 |
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