title: Conformational rearrangements to the intracellular open states of the LeuT and ApcT transporters are modulated by common mechanisms.
abstract: Recent crystallographic studies revealed that five transporter families without much sequence similarities among them have similar structure folds to LeuT, a bacterial neurotransmitter:sodium symporter homolog. The LeuT fold is characterized by an internal twofold structural pseudosymmetry. The transport cycle of some members of each of these families is dependent on a sodium gradient across the membrane, whereas in some others the role of sodium is mimicked by proton. We report on the identification of common structure-dynamics elements of the transporters with LeuT fold, which are recognizable in the conformational transitions related to function. The findings from comparative computational modeling and simulation studies of LeuT, and ApcT from the amino acid-polyamine-organocation transporter family define the intramolecular mechanisms by which Na+ binding couples to the transport process, and single out the lead/active role of TM1a in the transition to inward-open conformation. These mechanistic insights are derived in the context of collaborative investigations of LeuT dynamics with both single-molecule fluorescence and simulations that have produced excellent agreement of the dynamic details, and are found to be generalizable across the transporter families and to transcend sequence and motif similarities.
authors.affiliation: Department of Physiology and Biophysics, and HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University, New York, New York, USA. les2007@med.cornell.edu
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
mesh_terms: D001665:Binding Sites; D042541:Intracellular Space / Q000378:metabolism*; D008958:Models, Molecular; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation; D012964:Sodium / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D050480:Plasma Membrane Neurotransmitter Transport Proteins; D012964:Sodium