Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle

Cheng, MH and Bahar, I (2014) Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle. PLoS Computational Biology, 10 (10). ISSN 1553-734X

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Abstract

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).

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Details

Item Type:	Article
Status:	Published
Creators/Authors:	Creators Email Pitt Username ORCID Cheng, MH Bahar, I ivet.bahar@stonybrook.edu BAHAR
Contributors:	Contribution Contributors Name Email Pitt Username ORCID Editor de Groot, Bert L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
Date:	1 October 2014
Date Type:	Publication
Journal or Publication Title:	PLoS Computational Biology
Volume:	10
Number:	10
DOI or Unique Handle:	10.1371/journal.pcbi.1003879
Schools and Programs:	School of Medicine > Computational and Systems Biology
Refereed:	Yes
ISSN:	1553-734X
Other ID:	NLM PMC4191883
PubMed Central ID:	PMC4191883
PubMed ID:	25299050
Date Deposited:	12 May 2015 17:52
Last Modified:	17 Mar 2023 11:55
URI:	http://d-scholarship.pitt.edu/id/eprint/24029

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