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The molecular mechanism of sialic acid transport mediated by Sialin

Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 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 mutation...

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Autores principales: Hu, Wenxin, Chi, Congwu, Song, Kunhua, Zheng, Hongjin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858498/
https://www.ncbi.nlm.nih.gov/pubmed/36662855
http://dx.doi.org/10.1126/sciadv.ade8346
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author Hu, Wenxin
Chi, Congwu
Song, Kunhua
Zheng, Hongjin
author_facet Hu, Wenxin
Chi, Congwu
Song, Kunhua
Zheng, Hongjin
author_sort Hu, Wenxin
collection PubMed
description Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 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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spelling pubmed-98584982023-01-30 The molecular mechanism of sialic acid transport mediated by Sialin Hu, Wenxin Chi, Congwu Song, Kunhua Zheng, Hongjin Sci Adv Biomedicine and Life Sciences Malfunction of the sialic acid transporter caused by various genetic mutations in the SLC17A5 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. American Association for the Advancement of Science 2023-01-20 /pmc/articles/PMC9858498/ /pubmed/36662855 http://dx.doi.org/10.1126/sciadv.ade8346 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Hu, Wenxin
Chi, Congwu
Song, Kunhua
Zheng, Hongjin
The molecular mechanism of sialic acid transport mediated by Sialin
title The molecular mechanism of sialic acid transport mediated by Sialin
title_full The molecular mechanism of sialic acid transport mediated by Sialin
title_fullStr The molecular mechanism of sialic acid transport mediated by Sialin
title_full_unstemmed The molecular mechanism of sialic acid transport mediated by Sialin
title_short The molecular mechanism of sialic acid transport mediated by Sialin
title_sort molecular mechanism of sialic acid transport mediated by sialin
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9858498/
https://www.ncbi.nlm.nih.gov/pubmed/36662855
http://dx.doi.org/10.1126/sciadv.ade8346
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