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

Science Advances
Patrick S MerkleKasper D Rand

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.

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Citations

Apr 28, 2019·Molecular Biology and Evolution·She ZhangIvet Bahar
Oct 10, 2018·Nature Communications·Chloe MartensArgyris Politis
Sep 27, 2019·Frontiers in Molecular Biosciences·Deepthi JosephAravind Penmatsa
Mar 15, 2020·Protein Science : a Publication of the Protein Society·Chloe Martens, Argyris Politis
Apr 13, 2019·Nature Communications·Ingvar R MöllerKasper D Rand
Nov 18, 2020·Nature Chemical Biology·Francesco FiorentinoCarol V Robinson
Mar 29, 2019·Current Opinion in Structural Biology·Vikas Navratna, Eric Gouaux
Feb 28, 2020·Biophysical Journal·Richard T BradshawLucy R Forrest
Jul 25, 2021·International Journal of Molecular Sciences·Léni JodaitisChloé Martens
Aug 22, 2021·Nature Communications·Per PlengeClaus J Loland

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Methods Mentioned

BETA
scintillation proximity assay
electron paramagnetic resonance
FRET

Software Mentioned

Express
DynamX
LeuT
PLGS
HX

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