A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1
The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids’ pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A numb...
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2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037021004001 |
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doaj-759c1ae3170943f9a860bc4d543b7f8a2021-09-27T04:24:50ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011952465254A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1Pavlo Stehantsev0Artem Stetsenko1Mariia Nemchinova2Nanda Gowtham Aduri3Siewert J. Marrink4Cornelius Gati5Albert Guskov6Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The NetherlandsGroningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The NetherlandsGroningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The NetherlandsDepartment of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USAGroningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The NetherlandsDepartment of Biological Sciences, Bridge Institute, USC Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, USAGroningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands; Moscow Institute of Physics and Technology, Dolgoprudny, Russia; Corresponding author at: Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, The Netherlands.The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids’ pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A number of mutations in ASCT1 (E256K, G381R, R457W) have been linked to severe neurodevelopmental disorders, however in the absence of ASCT1 structure it is hard to understand their impact on substrate transport. To ameliorate that we have determined a cryo-EM structure of human ASCT1 at 4.2 Å resolution and performed functional transport assays and molecular dynamics simulations, which revealed that given mutations lead to the diminished transport capability of ASCT1 caused by instability of transporter and impeded transport cycle.http://www.sciencedirect.com/science/article/pii/S2001037021004001Membrane transporterSolute carrierCryo-EMMolecular dynamicsASCT1Structural biology |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Pavlo Stehantsev Artem Stetsenko Mariia Nemchinova Nanda Gowtham Aduri Siewert J. Marrink Cornelius Gati Albert Guskov |
| spellingShingle |
Pavlo Stehantsev Artem Stetsenko Mariia Nemchinova Nanda Gowtham Aduri Siewert J. Marrink Cornelius Gati Albert Guskov A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 Computational and Structural Biotechnology Journal Membrane transporter Solute carrier Cryo-EM Molecular dynamics ASCT1 Structural biology |
| author_facet |
Pavlo Stehantsev Artem Stetsenko Mariia Nemchinova Nanda Gowtham Aduri Siewert J. Marrink Cornelius Gati Albert Guskov |
| author_sort |
Pavlo Stehantsev |
| title |
A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 |
| title_short |
A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 |
| title_full |
A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 |
| title_fullStr |
A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 |
| title_full_unstemmed |
A structural view onto disease-linked mutations in the human neutral amino acid exchanger ASCT1 |
| title_sort |
structural view onto disease-linked mutations in the human neutral amino acid exchanger asct1 |
| publisher |
Elsevier |
| series |
Computational and Structural Biotechnology Journal |
| issn |
2001-0370 |
| publishDate |
2021-01-01 |
| description |
The ASCT1 transporter of the SLC1 family is largely involved in equilibration of neutral amino acids’ pools across the plasma membrane and plays a prominent role in the transport of both L- and D-isomers of serine, essential for the normal functioning of the central nervous system in mammals. A number of mutations in ASCT1 (E256K, G381R, R457W) have been linked to severe neurodevelopmental disorders, however in the absence of ASCT1 structure it is hard to understand their impact on substrate transport. To ameliorate that we have determined a cryo-EM structure of human ASCT1 at 4.2 Å resolution and performed functional transport assays and molecular dynamics simulations, which revealed that given mutations lead to the diminished transport capability of ASCT1 caused by instability of transporter and impeded transport cycle. |
| topic |
Membrane transporter Solute carrier Cryo-EM Molecular dynamics ASCT1 Structural biology |
| url |
http://www.sciencedirect.com/science/article/pii/S2001037021004001 |
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