Substrate-Na+ complex formation: coupling mechanism for gamma-aminobutyrate symporters.
Crystal structures of transmembrane transport proteins belonging to the important families of neurotransmitter-sodium symporters reveal how they transport neurotransmitters across membranes. Substrate-induced structural conformations of gated neurotransmitter-sodium symporters have been in the focus of research, however, a key question concerning the mechanism of Na(+) ion coupling remained unanswered. Homology models of human glial transporter subtypes of the major inhibitory neurotransmitter gamma-aminobutyric acid were built. In accordance with selectivity data for subtype 2 vs. 3, docking and molecular dynamics calculations suggest similar orthosteric substrate (inhibitor) conformations and binding crevices but distinguishable allosteric Zn(2+) ion binding motifs. Considering the occluded conformational states of glial human gamma-aminobutyric acid transporter subtypes, we found major semi-extended and minor ring-like conformations of zwitterionic gamma-aminobutyric acid in complex with Na(+) ion. The existence of the minor ring-like conformation of gamma-aminobutyric acid in complex with Na(+) ion may be attributed to the strengthening of the intramolecular H-bond by the electrostatic effect of Na(+) ion. Coupling substrate uptake into cells with the thermodynamically favorable Na(+) ion movement through substrate-Na(+) ion complex formation may be a mechanistic principle featuring transmembrane neurotransmitter-sodium symporter proteins.
Palló
Anna
A
Department of Neurochemistry, Institute of Biomolecular Chemistry, Chemical Research Center, Hungarian Academy of Sciences, Budapest, Hungary.
Simon
Agnes
A
Bencsura
Akos
A
Héja
László
L
Kardos
Julianna
J
D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D003461:Crystallography; D050485:GABA Plasma Membrane Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012964:Sodium / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism*
D050485:GABA Plasma Membrane Transport Proteins; C493416:SLC6A11 protein, human; C493418:SLC6A13 protein, human; D005680:gamma-Aminobutyric Acid; D012964:Sodium; D015032:Zinc