The allosteric mechanism of substrate-specific transport in SLC6 is mediated by a volumetric sensor. Academic Article uri icon

Overview

abstract

  • Neurotransmitter:sodium symporters (NSSs) in the SLC6 family terminate neurotransmission by coupling the thermodynamically favorable transport of ions to the thermodynamically unfavorable transport of neurotransmitter back into presynaptic neurons. Results from many structural, functional, and computational studies on LeuT, a bacterial NSS homolog, have provided critical insight into the mechanism of sodium-coupled transport, but the mechanism underlying substrate-specific transport rates is still not understood. We present a combination of molecular dynamics simulations, single-molecule fluorescence resonance energy transfer (smFRET) imaging, and measurements of Na+ binding and substrate transport that reveals an allosteric substrate specificity mechanism. In this mechanism, residues F259 and I359 in the substrate binding pocket couple the binding of substrate to Na+ release from the Na2 site by allosterically modulating the stability of a partially open, inward-facing state. We propose a model for transport selectivity in which residues F259 and I359 act as a volumetric sensor that inhibits the transport of bulky amino acids.

publication date

  • July 19, 2019

Research

keywords

  • Plasma Membrane Neurotransmitter Transport Proteins

Identity

PubMed Central ID

  • PMC6689989

Scopus Document Identifier

  • 85070206402

Digital Object Identifier (DOI)

  • 10.1016/j.neuropharm.2018.10.040

PubMed ID

  • 31324743

Additional Document Info

volume

  • 116

issue

  • 32