title: Unveiling the Mechanism of Arginine Transport through AdiC with Molecular Dynamics Simulations: The Guiding Role of Aromatic Residues.
abstract: Commensal and pathogenic enteric bacteria have developed several systems to adapt to proton leakage into the cytoplasm resulting from extreme acidic conditions. One such system involves arginine uptake followed by export of the decarboxylated product agmatine, carried out by the arginine/agmatine antiporter (AdiC), which thus works as a virtual proton pump. Here, using classical and targeted molecular dynamics, we investigated at the atomic level the mechanism of arginine transport through AdiC of E. coli. Overall, our MD simulation data clearly demonstrate that global rearrangements of several transmembrane segments are necessary but not sufficient for achieving transitions between structural states along the arginine translocation pathway. In particular, local structural changes, namely rotameric conversions of two aromatic residues, are needed to regulate access to both the outward- and inward-facing states. Our simulations have also enabled identification of a few residues, overwhelmingly aromatic, which are essential to guiding arginine in the course of its translocation. Most of them belong to gating elements whose coordinated motions contribute to the alternating access mechanism. Their conservation in all known E. coli acid resistance antiporters suggests that the transport mechanisms of these systems share common features. Last but not least, knowledge of the functional properties of AdiC can advance our understanding of the members of the amino acid-carbocation-polyamine superfamily, notably in eukaryotic cells.
authors.affiliation: Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Krammer
authors.affiliation: Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Brussels, Belgium.|Molecular Physiology of the Cell, Université Libre de Bruxelles (ULB), IBMM, Gosselies, Belgium.
authors.forename: Kassem
authors.initials: K
authors.lastname: Ghaddar
authors.affiliation: Molecular Physiology of the Cell, Université Libre de Bruxelles (ULB), IBMM, Gosselies, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: André
authors.affiliation: Structure et Fonction des Membranes Biologiques, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Martine
authors.identifier: http://orcid.org/0000-0003-3144-7828
authors.initials: M
authors.lastname: Prévost
mesh_terms: D000376:Agmatine / Q000737:chemistry* / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000737:chemistry* / Q000378:metabolism; D017920:Antiporters / Q000737:chemistry* / Q000378:metabolism; D001120:Arginine / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001692:Biological Transport; D004926:Escherichia coli / Q000737:chemistry* / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000378:metabolism; D015870:Gene Expression; D007700:Kinetics; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: C476528:AdiC protein, E coli; D026905:Amino Acid Transport Systems; D017920:Antiporters; D029968:Escherichia coli Proteins; D000376:Agmatine; D001120:Arginine