Abstract
The LeuT-fold superfamily includes secondary active transporters from different functional families, which share a common tertiary structure, despite having a remarkably low sequence similarity. By identifying the common structural and dynamical features upon principal component analysis of a comprehensive ensemble of 90 experimentally resolved structures and anisotropic network model evaluation of collective motions, we provide a unified point of view for understanding the reasons why this particular fold has been selected by evolution to accomplish such a broad spectrum of functions. The parallel identification of conserved sequence features, localized at specific sites of transmembrane helices, sheds light on the role of broken helices (TM1 and TM6 in LeuT) in promoting ion/substrate binding and allosteric interconversion between the outward- and inward-facing conformations of transporters. Finally, the determination of the dynamics landscape for the structural ensemble provides a promising framework for the classification of transporters based on their dynamics, and the characterization of the collective movements that favour multimerization.This article is part of a discussion meeting issue ‘Allostery and molecular machines’.
Highlights
Secondary active transporters translocate small molecules such as neurotransmitters, nutrients and metabolites across cellular membranes, using the energy provided by the co-transport or exchange of ions or other solutes down their electrochemical gradients
The present study focused on a superfamily of structural homologues, LeuT superfamily, that encompasses members from five families of transporters with different functions and low sequence identity
We first characterized their shared structural and dynamic characteristics, and proceeded to elucidate which features on a local or global scale, structural or dynamic, differentiate them to lead to different functions
Summary
Secondary active transporters translocate small molecules such as neurotransmitters, nutrients and metabolites across cellular membranes, using the energy provided by the co-transport (symport) or exchange (antiport) of ions or other solutes down their electrochemical gradients. They stabilize the OFS, IFS or intermediate/occluded state and sample a spectrum of conformational changes, during the transport cycle. While members of the same family (see the colour code) tend to cluster together, we note that within each family a certain degree of segregation between IF (upward triangle) and outward-facing (OF; downward triangle) states takes place, for instance in the case of BetP (in orange) and Mhp (in purple), consistent with the analogous separation for LeuT (blue) Such observation points to the fact that a common gating mechanism might be shared among members of the superfamily, and is well captured by the softest mode favoured by the common fold.
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