Successful prediction of substrate-binding pocket in SLC17 transporter sialin.

The Journal of Biological Chemistry
Nicolas PietrancostaB Gasnier

Abstract

Secondary active transporters from the SLC17 protein family are required for excitatory and purinergic synaptic transmission, sialic acid metabolism, and renal function, and several members are associated with inherited neurological or metabolic diseases. However, molecular tools to investigate their function or correct their genetic defects are limited or absent. Using structure-activity, homology modeling, molecular docking, and mutagenesis studies, we have located the substrate-binding site of sialin (SLC17A5), a lysosomal sialic acid exporter also recently implicated in exocytotic release of aspartate. Human sialin is defective in two inherited sialic acid storage diseases and is responsible for metabolic incorporation of the dietary nonhuman sialic acid N-glycolylneuraminic acid. We built cytosol-open and lumen-open three-dimensional models of sialin based on weak, but significant, sequence similarity with the glycerol-3-phosphate and fucose permeases from Escherichia coli, respectively. Molecular docking of 31 synthetic sialic acid analogues to both models was consistent with inhibition studies. Narrowing the sialic acid-binding site in the cytosol-open state by two phenylalanine to tyrosine mutations abrogated recognitio...Continue Reading

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Citations

Jan 3, 2018·Journal of Inherited Metabolic Disease·Pierre André GilorminiChristophe Biot
Jan 11, 2020·Biochimica Et Biophysica Acta. Biomembranes·Charles M Thompson, Chih-Kai Chao
Dec 8, 2019·Neuropharmacology·Odile PoirelNicolas Pietrancosta
Apr 17, 2021·Neuroscience Letters·Marjan HuizingUNKNOWN FSASD Consortium

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