Impact of pathogenic mutations of the GLUT1 glucose transporter on channel dynamics using ConsDYN enhanced sampling

Halima Mouhib, Akiko Higuchi, Sanne Abeln, Kei Yura, K. Anton Feenstra

Research output: Contribution to JournalArticleAcademic

Abstract

Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for the cell. 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. Methods: Predictions from SIFT and PolyPhen provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but no clear differentiation could be made by these methods between pathogenic and non-pathogenic mutations. Therefore, to identify the molecular effects on the transporter function, insight from molecular dynamic simulations is required. We studied a variety of pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ConsDYN’, which allows the sampling of both inward-open and outward-occluded states. To guarantee the sampling of large conformational changes, we only include conserved restraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between the two conformational states (≤1 Å difference). Results: We capture the ‘conserved dynamics’ between both states using ConsDYN. Simultaneously, it allowed us to considerably lower the computational costs of our study. This approach is sufficiently sensitive to capture the effect of different mutations, and 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 channel function, as it blocks the protein from sampling both conformational states.  Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein.
Original languageEnglish
Pages (from-to)322
JournalF1000Research
Volume8
DOIs
Publication statusPublished - 22 Mar 2019

Fingerprint

Facilitative Glucose Transport Proteins
Sampling
Mutation
Glucose Transporter Type 1
Molecular dynamics
Membrane Proteins
Defects
Molecules
Computer simulation
Costs
Proteins
Molecular Dynamics Simulation
Virulence
Epilepsy
Costs and Cost Analysis

Cite this

@article{1e7fad5aaf5c40cabad4ef64817adb6a,
title = "Impact of pathogenic mutations of the GLUT1 glucose transporter on channel dynamics using ConsDYN enhanced sampling",
abstract = "Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for the cell. 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. Methods: Predictions from SIFT and PolyPhen provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but no clear differentiation could be made by these methods between pathogenic and non-pathogenic mutations. Therefore, to identify the molecular effects on the transporter function, insight from molecular dynamic simulations is required. We studied a variety of pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ConsDYN’, which allows the sampling of both inward-open and outward-occluded states. To guarantee the sampling of large conformational changes, we only include conserved restraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between the two conformational states (≤1 {\AA} difference). Results: We capture the ‘conserved dynamics’ between both states using ConsDYN. Simultaneously, it allowed us to considerably lower the computational costs of our study. This approach is sufficiently sensitive to capture the effect of different mutations, and 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 channel function, as it blocks the protein from sampling both conformational states.  Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein.",
author = "Halima Mouhib and Akiko Higuchi and Sanne Abeln and Kei Yura and Feenstra, {K. Anton}",
year = "2019",
month = "3",
day = "22",
doi = "10.12688/f1000research.18553.1",
language = "English",
volume = "8",
pages = "322",
journal = "F1000Research",
issn = "2046-1402",
publisher = "F1000 Research Ltd.",

}

Impact of pathogenic mutations of the GLUT1 glucose transporter on channel dynamics using ConsDYN enhanced sampling. / Mouhib, Halima; Higuchi, Akiko; Abeln, Sanne; Yura, Kei; Feenstra, K. Anton.

In: F1000Research, Vol. 8, 22.03.2019, p. 322.

Research output: Contribution to JournalArticleAcademic

TY - JOUR

T1 - Impact of pathogenic mutations of the GLUT1 glucose transporter on channel dynamics using ConsDYN enhanced sampling

AU - Mouhib, Halima

AU - Higuchi, Akiko

AU - Abeln, Sanne

AU - Yura, Kei

AU - Feenstra, K. Anton

PY - 2019/3/22

Y1 - 2019/3/22

N2 - Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for the cell. 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. Methods: Predictions from SIFT and PolyPhen provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but no clear differentiation could be made by these methods between pathogenic and non-pathogenic mutations. Therefore, to identify the molecular effects on the transporter function, insight from molecular dynamic simulations is required. We studied a variety of pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ConsDYN’, which allows the sampling of both inward-open and outward-occluded states. To guarantee the sampling of large conformational changes, we only include conserved restraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between the two conformational states (≤1 Å difference). Results: We capture the ‘conserved dynamics’ between both states using ConsDYN. Simultaneously, it allowed us to considerably lower the computational costs of our study. This approach is sufficiently sensitive to capture the effect of different mutations, and 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 channel function, as it blocks the protein from sampling both conformational states.  Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein.

AB - Background: The solute carrier (SLC) family of membrane proteins is a large class of transporters for many small molecules that are vital for the cell. 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. Methods: Predictions from SIFT and PolyPhen provided an impression of the impact upon mutation in the highly conserved RXGRR motifs, but no clear differentiation could be made by these methods between pathogenic and non-pathogenic mutations. Therefore, to identify the molecular effects on the transporter function, insight from molecular dynamic simulations is required. We studied a variety of pathogenic and non-pathogenic mutations, using a newly developed coarse-grained simulation approach ‘ConsDYN’, which allows the sampling of both inward-open and outward-occluded states. To guarantee the sampling of large conformational changes, we only include conserved restraints of the elastic network introduced upon coarse-graining, which showed similar reference distances between the two conformational states (≤1 Å difference). Results: We capture the ‘conserved dynamics’ between both states using ConsDYN. Simultaneously, it allowed us to considerably lower the computational costs of our study. This approach is sufficiently sensitive to capture the effect of different mutations, and 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 channel function, as it blocks the protein from sampling both conformational states.  Conclusions: Using our approach, we can explain the pathogenicity of the mutation G91D when we observe the configurations of the transmembrane helices, suggesting that their relative position is crucial for the correct functioning of the GLUT1 protein.

UR - http://www.mendeley.com/research/impact-pathogenic-mutations-glut1-glucose-transporter-channel-dynamics-using-consdyn-enhanced-sampli

U2 - 10.12688/f1000research.18553.1

DO - 10.12688/f1000research.18553.1

M3 - Article

VL - 8

SP - 322

JO - F1000Research

JF - F1000Research

SN - 2046-1402

ER -