Partial Unwinding of Transmembrane Helices Facilitates Alternating Access in the Neurotransmitter:Sodium Symporter LeuT
2017
The prokaryotic neurotransmitter:sodium symporter (NSS) LeuT from Aquifex aeolicus is an established structural model for mammalian NSS counterparts. Here, 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 solution-phase dynamics associated with transition of the transporter between outward- and inward-facing configurations in a Na + - as well as K + -dependent manner. The results suggest that partial unwinding of transmembrane helices 1/5/6/7 drive LeuT from a substrate-bound, outward-facing occluded conformation towards an inward-facing open state. We thereby envisage that substrate release is facilitated by formation of two distinct solvent pathways, which mediate access to the Na + and substrate binding sites.
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