title: Allosteric Mechanisms of Molecular Machines at the Membrane: Transport by Sodium-Coupled Symporters.
abstract: Solute transport across cell membranes is ubiquitous in biology as an essential physiological process. Secondary active transporters couple the unfavorable process of solute transport against its concentration gradient to the energetically favorable transport of one or several ions. The study of such transporters over several decades indicates that their function involves complex allosteric mechanisms that are progressively being revealed in atomistic detail. We focus on two well-characterized sodium-coupled symporters: the bacterial amino acid transporter LeuT, which is the prototype for the "gated pore" mechanism in the mammalian synaptic monoamine transporters, and the archaeal GltPh, which is the prototype for the "elevator" mechanism in the mammalian excitatory amino acid transporters. We present the evidence for the role of allostery in the context of a quantitative formalism that can reconcile biochemical and biophysical data and thereby connects directly to recent insights into the molecular structure and dynamics of these proteins. We demonstrate that, while the structures and mechanisms of these transporters are very different, the available data suggest a common role of specific models of allostery in their functions. We argue that such allosteric mechanisms appear essential not only for sodium-coupled symport in general but also for the function of other types of molecular machines in the membrane.
authors.affiliation: Department of Physiology and Biophysics, ‡HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Michael V
authors.initials: MV
authors.lastname: LeVine
authors.affiliation: Department of Physiology and Biophysics, ‡HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Michel A
authors.initials: MA
authors.lastname: Cuendet
authors.affiliation: Department of Physiology and Biophysics, ‡HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: George
authors.initials: G
authors.lastname: Khelashvili
authors.affiliation: Department of Physiology and Biophysics, ‡HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University , New York, New York 10065, United States.
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D000494:Allosteric Regulation; D026905:Amino Acid Transport Systems / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D012964:Sodium / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D026905:Amino Acid Transport Systems; D012964:Sodium