التفاصيل البيبلوغرافية
| العنوان: |
Dynamics of SLC25A51 reveal preference for oxidized NAD+ and substrate led transport. |
| المؤلفون: |
Goyal, Shivansh, Paspureddi, Akhilesh, Lu, Mu‐Jie, Chan, Hsin‐Ru, Lyons, Scott N, Wilson, Crystal N, Niere, Marc, Ziegler, Mathias, Cambronne, Xiaolu A |
| المصدر: |
EMBO Reports; 10/9/2023, Vol. 24 Issue 10, p1-14, 14p |
| مستخلص: |
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. Synopsis: This study reveals how human mitochondrial transporter SLC25A51 distinguishes its cognate ligand, oxidized NAD+, and identifies a requirement for bound membrane phospholipid cardiolipin. Inaugural description of an NAD+ binding site among mitochondrial carriers.Evidence for a ligand‐led gate opening mechanism.Requirement of bound cardiolipin for activity.Potential for uniport activity in specific contexts. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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