Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations]
Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for cellular function. Several pathogenic mutations are reported in the glucose transporter subfamily SLC2, causing Glut1-deficiency syndrome (GLUT1DS1, GLUT1DS2)...
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F1000 Research Ltd
2022-06-01
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| author | K. Anton Feenstra Akiko Higuchi Kei Yura Sanne Abeln Halima Mouhib |
| author_facet | K. Anton Feenstra Akiko Higuchi Kei Yura Sanne Abeln Halima Mouhib |
| author_sort | K. Anton Feenstra |
| collection | DOAJ |
| description | Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for cellular function. Several pathogenic mutations are reported in the glucose transporter subfamily SLC2, causing Glut1-deficiency syndrome (GLUT1DS1, GLUT1DS2), epilepsy (EIG2) and cryohydrocytosis with neurological defects (Dystonia-9). Understanding the link between these mutations and transporter dynamics is crucial to elucidate their role in the dysfunction of the underlying transport mechanism, which we investigate using molecular dynamics simulations. Methods: We studied pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ComDYN’, which captures the ‘COMmon constraints DYNamics’ between both states of the solute carrier protein. To guarantee the sampling of large conformational changes, we only include common constraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between both conformational states (≤1 Å difference). Results: ComDYN is computationally efficient and sufficiently sensitive to capture effects of different mutations. Our results clearly indicate that the pathogenic mutation in GLUT1, G91D, situated at the highly conserved RXGRR motif between helices 2 and 3, has a strong impact on transporter function, as it blocks the protein from sampling both conformational states. In comparison, predictions from SIFT and PolyPhen only provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but yielded no clear differentiation between pathogenic and non-pathogenic mutations. Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D and some of the effects of other known pathogenic mutations, when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein. To fully understand the impact of other mutations in the future, it is necessary to consider the effect of ligands, e.g., glucose, within the transport mechanism. |
| format | Article |
| id | doaj-art-e77ce8190c6c4bb692276bad561e164f |
| institution | Kabale University |
| issn | 2046-1402 |
| language | English |
| publishDate | 2022-06-01 |
| publisher | F1000 Research Ltd |
| record_format | Article |
| series | F1000Research |
| spelling | doaj-art-e77ce8190c6c4bb692276bad561e164f2025-01-30T01:00:00ZengF1000 Research LtdF1000Research2046-14022022-06-018133928Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations]K. Anton Feenstra0https://orcid.org/0000-0001-6755-9667Akiko Higuchi1Kei Yura2Sanne Abeln3https://orcid.org/0000-0002-2779-7174Halima Mouhib4Dept. Computer Science, Integrative Bioinformatics, Vrije Universiteit, Amsterdam, The NetherlandsGraduate School of Frontier Sciences, The University of Tokyo, Tokyo, JapanGraduate School of Humanities and Sciences, Ochanomizu University, Tokyo, JapanDept. Computer Science, Integrative Bioinformatics, Vrije Universiteit, Amsterdam, The NetherlandsLaboratoire Modélisation et Simulation Multi Echelle (MSME) - UMR 8208 CNRS, Université Paris-Est, Champs-sur-Marne, FranceBackground: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for cellular function. Several pathogenic mutations are reported in the glucose transporter subfamily SLC2, causing Glut1-deficiency syndrome (GLUT1DS1, GLUT1DS2), epilepsy (EIG2) and cryohydrocytosis with neurological defects (Dystonia-9). Understanding the link between these mutations and transporter dynamics is crucial to elucidate their role in the dysfunction of the underlying transport mechanism, which we investigate using molecular dynamics simulations. Methods: We studied pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ComDYN’, which captures the ‘COMmon constraints DYNamics’ between both states of the solute carrier protein. To guarantee the sampling of large conformational changes, we only include common constraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between both conformational states (≤1 Å difference). Results: ComDYN is computationally efficient and sufficiently sensitive to capture effects of different mutations. Our results clearly indicate that the pathogenic mutation in GLUT1, G91D, situated at the highly conserved RXGRR motif between helices 2 and 3, has a strong impact on transporter function, as it blocks the protein from sampling both conformational states. In comparison, predictions from SIFT and PolyPhen only provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but yielded no clear differentiation between pathogenic and non-pathogenic mutations. Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D and some of the effects of other known pathogenic mutations, when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein. To fully understand the impact of other mutations in the future, it is necessary to consider the effect of ligands, e.g., glucose, within the transport mechanism.https://f1000research.com/articles/8-322/v2GLUT1 glucose transporter deficiency syndrome Human glucose transporters SLC transporter family transport mechanism molecular dynamics simulation Martini force fieldeng |
| spellingShingle | K. Anton Feenstra Akiko Higuchi Kei Yura Sanne Abeln Halima Mouhib Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] F1000Research GLUT1 glucose transporter deficiency syndrome Human glucose transporters SLC transporter family transport mechanism molecular dynamics simulation Martini force field eng |
| title | Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full | Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_fullStr | Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_full_unstemmed | Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_short | Impact of pathogenic mutations of the GLUT1 glucose transporter on solute carrier dynamics using ComDYN enhanced sampling [version 2; peer review: 2 approved, 1 approved with reservations] |
| title_sort | impact of pathogenic mutations of the glut1 glucose transporter on solute carrier dynamics using comdyn enhanced sampling version 2 peer review 2 approved 1 approved with reservations |
| topic | GLUT1 glucose transporter deficiency syndrome Human glucose transporters SLC transporter family transport mechanism molecular dynamics simulation Martini force field eng |
| url | https://f1000research.com/articles/8-322/v2 |
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