Principles of Alternating Access in LeuT-fold Transporters: Commonalities and Divergences

Found in all domains of life, transporters belonging to the LeuT-fold class mediate the import and exchange of hydrophilic and charged compounds such as amino acids, metals, and sugar molecules. Nearly two decades of investigations on the eponymous bacterial transporter LeuT have yielded a library of high-resolution snapshots of its conformational cycle linked by solution-state experimental data obtained from multiple techniques. In parallel, its topology has been observed in symporters and antiporters characterized by a spectrum of substrate specificities and coupled to gradients of distinct ions. Here we review and compare mechanistic models of transport for LeuT, its well-studied homologs, as well as functionally distant members of the fold, emphasizing the commonalities and divergences in alternating access and the corresponding energy landscapes. Our integrated summary illustrates how fold conservation, a hallmark of the LeuT fold, coincides with divergent choreographies of alternating access that nevertheless capitalize on recurrent structural motifs. In addition, it highlights the knowledge gap that hinders the leveraging of the current body of research into detailed mechanisms of transport for this important class of membrane proteins.