National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM126626
United States
National Institutes of Health/National Institute on Aging (NIH/NIA)
AG064672
United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)
HL133230
United States
Citation
Journal: Sci Adv / Year: 2023 Title: The molecular mechanism of sialic acid transport mediated by Sialin. Authors: Wenxin Hu / Congwu Chi / Kunhua Song / Hongjin Zheng / Abstract: Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage ...Malfunction of the sialic acid transporter caused by various genetic mutations in the gene encoding Sialin leads to a spectrum of neurodegenerative conditions called free sialic acid storage disorders. Unfortunately, how Sialin transports sialic acid/proton (H) and how pathogenic mutations impair its function are poorly defined. Here, we present the structure of human Sialin in an inward-facing partially open conformation determined by cryo-electron microscopy, representing the first high-resolution structure of any human SLC17 member. Our analysis reveals two unique features in Sialin: (i) The H coupling/sensing requires two highly conserved Glu residues (E171 and E175) instead of one (E175) as implied in previous studies; and (ii) the normal function of Sialin requires the stabilization of a cytosolic helix, which has not been noticed in the literature. By mapping known pathogenic mutations, we provide mechanistic explanations for corresponding functional defects. We propose a structure-based mechanism for sialic acid transport mediated by Sialin.
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