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- EMDB-27755: Molecular Mechanism of Sialic Acid Transport Mediated by Sialin -

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Basic information

Entry
Database: EMDB / ID: EMD-27755
TitleMolecular Mechanism of Sialic Acid Transport Mediated by Sialin
Map datahuman Sialin
Sample
  • Complex: Sialin complex with Fab 8B1
    • Protein or peptide: Sialin
Function / homology
Function and homology information


sialic acid:proton symporter activity / sialic acid transport / D-glucuronate transmembrane transporter activity / Defective SLC17A5 causes Salla disease (SD) and ISSD / Organic anion transporters / sialic acid transmembrane transporter activity / carbohydrate:proton symporter activity / Sialic acid metabolism / amino acid transport / monoatomic anion transport ...sialic acid:proton symporter activity / sialic acid transport / D-glucuronate transmembrane transporter activity / Defective SLC17A5 causes Salla disease (SD) and ISSD / Organic anion transporters / sialic acid transmembrane transporter activity / carbohydrate:proton symporter activity / Sialic acid metabolism / amino acid transport / monoatomic anion transport / transmembrane transporter activity / monoatomic ion transport / response to bacterium / synaptic vesicle membrane / lysosome / lysosomal membrane / membrane / plasma membrane / cytosol
Similarity search - Function
Major facilitator superfamily / Major Facilitator Superfamily / Major facilitator superfamily domain / Major facilitator superfamily (MFS) profile. / MFS transporter superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsHu W / Zheng H
Funding support United States, 3 items
OrganizationGrant numberCountry
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
CitationJournal: 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.
History
DepositionAug 1, 2022-
Header (metadata) releaseJan 25, 2023-
Map releaseJan 25, 2023-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27755.png

Downloads & links

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Map

FileDownload / File: emd_27755.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman Sialin
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.155
Minimum - Maximum-0.68034726 - 1.0306395
Average (Standard dev.)0.0021572872 (±0.017529117)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 265.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B

Fileemd_27755_half_map_1.map
Annotationhalf map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_27755_half_map_2.map
Annotationhalf map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Sialin complex with Fab 8B1

EntireName: Sialin complex with Fab 8B1
Components
  • Complex: Sialin complex with Fab 8B1
    • Protein or peptide: Sialin

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Supramolecule #1: Sialin complex with Fab 8B1

SupramoleculeName: Sialin complex with Fab 8B1 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sialin

MacromoleculeName: Sialin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.684168 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MRSPVRDLAR NDGEESTDRT PLLPGAPRAE AAPVCCSARY NLAILAFFGF FIVYALRVNL SVALVDMVDS NTTLEDNRTS KACPEHSAP IKVHHNQTGK KYQWDAETQG WILGSFFYGY IITQIPGGYV ASKIGGKMLL GFGILGTAVL TLFTPIAADL G VGPLIVLR ...String:
MRSPVRDLAR NDGEESTDRT PLLPGAPRAE AAPVCCSARY NLAILAFFGF FIVYALRVNL SVALVDMVDS NTTLEDNRTS KACPEHSAP IKVHHNQTGK KYQWDAETQG WILGSFFYGY IITQIPGGYV ASKIGGKMLL GFGILGTAVL TLFTPIAADL G VGPLIVLR ALEGLGEGVT FPAMHAMWSS WAPPLERSKL LSISYAGAQL GTVISLPLSG IICYYMNWTY VFYFFGTIGI FW FLLWIWL VSDTPQKHKR ISHYEKEYIL SSLRNQLSSQ KSVPWVPILK SLPLWAIVVA HFSYNWTFYT LLTLLPTYMK EIL RFNVQE NGFLSSLPYL GSWLCMILSG QAADNLRAKW NFSTLCVRRI FSLIGMIGPA VFLVAAGFIG CDYSLAVAFL TIST TLGGF CSSGFSINHL DIAPSYAGIL LGITNTFATI PGMVGPVIAK SLTPDNTVGE WQTVFYIAAA INVFGAIFFT LFAKG EVQN WALNDHHGHR H

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.2 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 394078

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