Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle.
Neurotransmitter: sodium symporters (NSSs) regulate neuronal signal transmission by clearing excess neurotransmitters from the synapse, assisted by the co-transport of sodium ions. Extensive structural data have been collected in recent years for several members of the NSS family, which opened the w...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-10-01
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| Series: | PLoS Computational Biology |
| Online Access: | http://europepmc.org/articles/PMC4191883?pdf=render |
| _version_ | 1828180099004891136 |
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| author | Mary Hongying Cheng Ivet Bahar |
| author_facet | Mary Hongying Cheng Ivet Bahar |
| author_sort | Mary Hongying Cheng |
| collection | DOAJ |
| description | Neurotransmitter: sodium symporters (NSSs) regulate neuronal signal transmission by clearing excess neurotransmitters from the synapse, assisted by the co-transport of sodium ions. Extensive structural data have been collected in recent years for several members of the NSS family, which opened the way to structure-based studies for a mechanistic understanding of substrate transport. Leucine transporter (LeuT), a bacterial orthologue, has been broadly adopted as a prototype in these studies. This goal has been elusive, however, due to the complex interplay of global and local events as well as missing structural data on LeuT N-terminal segment. We provide here for the first time a comprehensive description of the molecular events leading to substrate/Na+ release to the postsynaptic cell, including the structure and dynamics of the N-terminal segment using a combination of molecular simulations. Substrate and Na+-release follows an influx of water molecules into the substrate/Na+-binding pocket accompanied by concerted rearrangements of transmembrane helices. A redistribution of salt bridges and cation-π interactions at the N-terminal segment prompts substrate release. Significantly, substrate release is followed by the closure of the intracellular gate and a global reconfiguration back to outward-facing state to resume the transport cycle. Two minimally hydrated intermediates, not structurally resolved to date, are identified: one, substrate-bound, stabilized during the passage from outward- to inward-facing state (holo-occluded), and another, substrate-free, along the reverse transition (apo-occluded). |
| first_indexed | 2024-04-12T05:39:25Z |
| format | Article |
| id | doaj.art-f6b57911f99d4f989a8ffe723983eb13 |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-12T05:39:25Z |
| publishDate | 2014-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-f6b57911f99d4f989a8ffe723983eb132022-12-22T03:45:43ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582014-10-011010e100387910.1371/journal.pcbi.1003879Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle.Mary Hongying ChengIvet BaharNeurotransmitter: sodium symporters (NSSs) regulate neuronal signal transmission by clearing excess neurotransmitters from the synapse, assisted by the co-transport of sodium ions. Extensive structural data have been collected in recent years for several members of the NSS family, which opened the way to structure-based studies for a mechanistic understanding of substrate transport. Leucine transporter (LeuT), a bacterial orthologue, has been broadly adopted as a prototype in these studies. This goal has been elusive, however, due to the complex interplay of global and local events as well as missing structural data on LeuT N-terminal segment. We provide here for the first time a comprehensive description of the molecular events leading to substrate/Na+ release to the postsynaptic cell, including the structure and dynamics of the N-terminal segment using a combination of molecular simulations. Substrate and Na+-release follows an influx of water molecules into the substrate/Na+-binding pocket accompanied by concerted rearrangements of transmembrane helices. A redistribution of salt bridges and cation-π interactions at the N-terminal segment prompts substrate release. Significantly, substrate release is followed by the closure of the intracellular gate and a global reconfiguration back to outward-facing state to resume the transport cycle. Two minimally hydrated intermediates, not structurally resolved to date, are identified: one, substrate-bound, stabilized during the passage from outward- to inward-facing state (holo-occluded), and another, substrate-free, along the reverse transition (apo-occluded).http://europepmc.org/articles/PMC4191883?pdf=render |
| spellingShingle | Mary Hongying Cheng Ivet Bahar Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. PLoS Computational Biology |
| title | Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. |
| title_full | Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. |
| title_fullStr | Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. |
| title_full_unstemmed | Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. |
| title_short | Complete mapping of substrate translocation highlights the role of LeuT N-terminal segment in regulating transport cycle. |
| title_sort | complete mapping of substrate translocation highlights the role of leut n terminal segment in regulating transport cycle |
| url | http://europepmc.org/articles/PMC4191883?pdf=render |
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