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Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport.
Goyal, Shivansh; Paspureddi, Akhilesh; Lu, Mu-Jie; Chan, Hsin-Ru; Lyons, Scott N; Wilson, Crystal N; Niere, Marc; Ziegler, Mathias; Cambronne, Xiaolu A.
Afiliación
  • Goyal S; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • Paspureddi A; Department of Chemical Engineering, University of Texas at Austin, Austin, TX, USA.
  • Lu MJ; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • Chan HR; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • Lyons SN; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • Wilson CN; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
  • Niere M; Department of Biomedicine, University of Bergen, Bergen, Norway.
  • Ziegler M; Department of Biomedicine, University of Bergen, Bergen, Norway.
  • Cambronne XA; Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, USA.
EMBO Rep ; 24(10): e56596, 2023 10 09.
Article en En | MEDLINE | ID: mdl-37575034
SLC25A51 is a member of the mitochondrial carrier family (MCF) but lacks key residues that contribute to the mechanism of other nucleotide MCF transporters. Thus, how SLC25A51 transports NAD+ across the inner mitochondrial membrane remains unclear. To elucidate its mechanism, we use Molecular Dynamics simulations to reconstitute SLC25A51 homology models into lipid bilayers and to generate hypotheses to test. We observe spontaneous binding of cardiolipin phospholipids to three distinct sites on the exterior of SLC25A51's central pore and find that mutation of these sites impairs cardiolipin binding and transporter activity. We also observe that stable formation of the required matrix gate is controlled by a single salt bridge. We identify binding sites in SLC25A51 for NAD+ and show that its selectivity for NAD+ is guided by an electrostatic interaction between the charged nicotinamide ring in the ligand and a negatively charged patch in the pore. In turn, interaction of NAD+ with interior residue E132 guides the ligand to dynamically engage and weaken the salt bridge gate, representing a ligand-induced initiation of transport.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cardiolipinas / NAD Aspecto: Patient_preference Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cardiolipinas / NAD Aspecto: Patient_preference Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido