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Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis

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Szöllősi,  Daniel
Department of Theoretical and Computational Biophysics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Protein Science - 2023 - Clarke
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Citation

Clarke, A., Farr, C. V., El-Kasaby, A., Szöllősi, D., Freissmuth, M., Sucic, S., et al. (2024). Probing binding and occlusion of substrate in the human creatine transporter-1 by computation and mutagenesis. Protein Science, 33(1): e4842. doi:10.1002/pro.4842.


Cite as: https://hdl.handle.net/21.11116/0000-000E-3915-B
Abstract
In chordates, energy buffering is achieved in part through phosphocreatine, which requires cellular uptake of creatine by the membrane-embedded creatine transporter (CRT1/SLC6A8). Mutations in human slc6a8 lead to creatine transporter deficiency syndrome, for which there is only limited treatment. Here, we used a combined homology modeling, molecular dynamics, and experimental approach to generate a structural model of CRT1. Our observations support the following conclusions: contrary to previous proposals, C144, a key residue in the substrate binding site, is not present in a charged state. Similarly, the side chain D458 must be present in a protonated form to maintain the structural integrity of CRT1. Finally, we identified that the interaction chain Y148-creatine-Na+ is essential to the process of occlusion, which occurs via a “hold-and-pull” mechanism. The model should be useful to study the impact of disease-associated point mutations on the folding of CRT1 and identify approaches which correct folding-deficient mutants.