8dwi
From Proteopedia
Molecular Mechanism of Sialic Acid Transport Mediated by Sialin
Structural highlights
DiseaseS17A5_HUMAN Salla disease;Intermediate severe Salla disease;Free sialic acid storage disease, infantile form. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionS17A5_HUMAN Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport (PubMed:15510212, PubMed:21781115, PubMed:22778404, PubMed:23889254). Electroneutral proton-coupled acidic monosaccharide symporter, with a sugar to proton stoichiometry of 1:1. Exports glucuronic acid and free sialic acid derived from sialoglycoconjugate degradation out of lysosomes, driven by outwardly directed lysosomal pH gradient. May regulate lysosome function and metabolism of sialylated conjugates that impact oligodendrocyte lineage differentiation and myelinogenesis in the central nervous system (By similarity) (PubMed:15510212, PubMed:21781115, PubMed:22778404, PubMed:23889254). Electrogenic proton-coupled nitrate symporter that transports nitrate ions across the basolateral membrane of salivary gland acinar cells, with nitrate to proton stoichiometry of 2:1. May contribute to nitrate clearance from serum by salivary glands, where it is further concentrated and secreted in the saliva (PubMed:22778404). Uses membrane potential to drive the uptake of acidic amino acids and peptides into synaptic vesicles. Responsible for synaptic vesicular storage of L-aspartate and L-glutamate in pinealocytes as well as vesicular uptake of N-acetyl-L-aspartyl-L-glutamate neuropeptide, relevant to aspartegic-associated glutamatergic neurotransmission and activation of metabotropic receptors that inhibit subsequent transmitter release (By similarity) (PubMed:21781115, PubMed:22778404, PubMed:23889254).[UniProtKB:Q5Q0U0][UniProtKB:Q8BN82][1] [2] [3] [4] Receptor for CM101, a polysaccharide produced by group B Streptococcus with antipathoangiogenic properties.[UniProtKB:Q9MZD1] Publication Abstract from PubMedMalfunction 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. The molecular mechanism of sialic acid transport mediated by Sialin.,Hu W, Chi C, Song K, Zheng H Sci Adv. 2023 Jan 20;9(3):eade8346. doi: 10.1126/sciadv.ade8346. Epub 2023 Jan , 20. PMID:36662855[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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