title: Cytoplasmic permeation pathway of neurotransmitter transporters.
abstract: Ion-coupled solute transporters are responsible for transporting nutrients, ions, and signaling molecules across a variety of biological membranes. Recent high-resolution crystal structures of several transporters from protein families that were previously thought to be unrelated show common structural features indicating a large structural family representing transporters from all kingdoms of life. This review describes studies that led to an understanding of the conformational changes required for solute transport in this family. The first structure in this family showed the bacterial amino acid transporter LeuT, which is homologous to neurotransmitter transporters, in an extracellularly oriented conformation with a molecule of leucine occluded at the substrate site. Studies with the mammalian serotonin transporter identified positions, buried in the LeuT structure, that defined a potential pathway leading from the cytoplasm to the substrate binding site. Modeling studies utilized an inverted structural repeat within the LeuT crystal structure to predict the conformation of LeuT in which the cytoplasmic permeation pathway, consisting of positions identified in SERT, was open for diffusion of the substrate to the cytoplasm. From the difference between the model and the crystal structures, a simple "rocking bundle" mechanism was proposed, in which a four-helix bundle changed its orientation with respect to the rest of the protein to close the extracellular pathway and open the cytoplasmic one. Subsequent crystal structures from structurally related proteins provide evidence supporting this model for transport.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States. gary.rudnick@yale.edu
authors.forename: Gary
authors.initials: G
authors.lastname: Rudnick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002463:Cell Membrane Permeability / Q000235:genetics / Q000502:physiology*; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007930:Leucine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D050479:Neurotransmitter Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D050479:Neurotransmitter Transport Proteins; D007930:Leucine