Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps
Objective Glutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting h...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Springer US
2024
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| Online Access: | https://hdl.handle.net/1721.1/157515 |
| _version_ | 1824458432367820800 |
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| author | Karagöl, Alper Karagöl, Taner Li, Mengke Zhang, Shuguang |
| author2 | Massachusetts Institute of Technology. Media Laboratory |
| author_facet | Massachusetts Institute of Technology. Media Laboratory Karagöl, Alper Karagöl, Taner Li, Mengke Zhang, Shuguang |
| author_sort | Karagöl, Alper |
| collection | MIT |
| description | Objective Glutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting heteromerization promises an effective approach for modulator design. On the other hand, the dynamic nature of transcription allows for the generation of transporter isoforms in structurally distinct manners. Methods The potential isoforms were identified through the analysis of computationally generated gene-centric isoform maps. The conserved features of isoform sequences were revealed by computational chemistry methods and subsequent structural analysis of AlphaFold2 predictions. Truncated isoforms were further subjected to a wide range of docking analyses, 50ns molecular dynamics simulations, and evolutionary coupling analyses. Results Energetic landscapes of isoform-canonical transporter complexes suggested an inhibitory potential of truncated isoforms on glutamate transporter bio-assembly. Moreover, isoforms that mimic the trimerization domain (in particular, TM2 helices) exhibited stronger interactions with canonical transporters, underscoring the role of transmembrane helices in isoform interactions. Additionally, self-assembly dynamics observed in truncated isoforms mimicking canonical TM5 helices indicate a potential protective role against unwanted interactions with canonical transporters. Conclusion Our computational studies on glutamate transporters offer insights into the roles of alternative splicing on protein interactions and identifies potential drug targets for physiological or pathological processes. |
| first_indexed | 2025-02-19T04:25:48Z |
| format | Article |
| id | mit-1721.1/157515 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2025-02-19T04:25:48Z |
| publishDate | 2024 |
| publisher | Springer US |
| record_format | dspace |
| spelling | mit-1721.1/1575152025-01-08T04:15:16Z Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps Karagöl, Alper Karagöl, Taner Li, Mengke Zhang, Shuguang Massachusetts Institute of Technology. Media Laboratory Objective Glutamate transporters play a key role in central nervous system physiology by maintaining excitatory neurotransmitter homeostasis. Biological assemblies of the transporters, consisting of cyclic homotrimers, emerge as a crucial aspect of glutamate transporter modulation. Hence targeting heteromerization promises an effective approach for modulator design. On the other hand, the dynamic nature of transcription allows for the generation of transporter isoforms in structurally distinct manners. Methods The potential isoforms were identified through the analysis of computationally generated gene-centric isoform maps. The conserved features of isoform sequences were revealed by computational chemistry methods and subsequent structural analysis of AlphaFold2 predictions. Truncated isoforms were further subjected to a wide range of docking analyses, 50ns molecular dynamics simulations, and evolutionary coupling analyses. Results Energetic landscapes of isoform-canonical transporter complexes suggested an inhibitory potential of truncated isoforms on glutamate transporter bio-assembly. Moreover, isoforms that mimic the trimerization domain (in particular, TM2 helices) exhibited stronger interactions with canonical transporters, underscoring the role of transmembrane helices in isoform interactions. Additionally, self-assembly dynamics observed in truncated isoforms mimicking canonical TM5 helices indicate a potential protective role against unwanted interactions with canonical transporters. Conclusion Our computational studies on glutamate transporters offer insights into the roles of alternative splicing on protein interactions and identifies potential drug targets for physiological or pathological processes. 2024-11-08T16:27:02Z 2024-11-08T16:27:02Z 2024-11-01 2024-11-03T04:17:45Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/157515 Karagöl, A., Karagöl, T., Li, M. et al. Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps. Pharm Res (2024). PUBLISHER_CC en 10.1007/s11095-024-03786-z Pharmaceutical Research Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf Springer US Springer US |
| spellingShingle | Karagöl, Alper Karagöl, Taner Li, Mengke Zhang, Shuguang Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title | Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title_full | Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title_fullStr | Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title_full_unstemmed | Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title_short | Inhibitory Potential of the Truncated Isoforms on Glutamate Transporter Oligomerization Identified by Computational Analysis of Gene-Centric Isoform Maps |
| title_sort | inhibitory potential of the truncated isoforms on glutamate transporter oligomerization identified by computational analysis of gene centric isoform maps |
| url | https://hdl.handle.net/1721.1/157515 |
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