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Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT.


ABSTRACT: LeuT, a prokaryotic member of the neurotransmitter:sodium symporter (NSS) family, is an established structural model for mammalian NSS counterparts. We investigate the substrate translocation mechanism of LeuT by measuring the solution-phase structural dynamics of the transporter in distinct functional states by hydrogen/deuterium exchange mass spectrometry (HDX-MS). Our HDX-MS data pinpoint LeuT segments involved in substrate transport and reveal for the first time a comprehensive and detailed view of the dynamics associated with transition of the transporter between outward- and inward-facing configurations in a Na+- and K+-dependent manner. The results suggest that partial unwinding of transmembrane helices 1/5/6/7 drives LeuT from a substrate-bound, outward-facing occluded conformation toward an inward-facing open state. These hitherto unknown, large-scale conformational changes in functionally important transmembrane segments, observed for LeuT in detergent-solubilized form and when embedded in a native-like phospholipid bilayer, could be of physiological relevance for the translocation process.

SUBMITTER: Merkle PS 

PROVIDER: S-EPMC5947982 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT.

Merkle Patrick S PS   Gotfryd Kamil K   Cuendet Michel A MA   Leth-Espensen Katrine Z KZ   Gether Ulrik U   Loland Claus J CJ   Rand Kasper D KD  

Science advances 20180511 5


LeuT, a prokaryotic member of the neurotransmitter:sodium symporter (NSS) family, is an established structural model for mammalian NSS counterparts. We investigate the substrate translocation mechanism of LeuT by measuring the solution-phase structural dynamics of the transporter in distinct functional states by hydrogen/deuterium exchange mass spectrometry (HDX-MS). Our HDX-MS data pinpoint LeuT segments involved in substrate transport and reveal for the first time a comprehensive and detailed  ...[more]

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