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- PDB-8dwi: Molecular Mechanism of Sialic Acid Transport Mediated by Sialin -

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Basic information

Entry
Database: PDB / ID: 8dwi
TitleMolecular Mechanism of Sialic Acid Transport Mediated by Sialin
ComponentsSialin
KeywordsMEMBRANE PROTEIN / sialic acid transport / solute carrier transporter
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsHu, W. / Zheng, H.
Funding support United States, 3items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 25, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 2.0Feb 22, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Refinement description / Source and taxonomy / Structure summary
Category: atom_site / em_software ...atom_site / em_software / entity / entity_poly / entity_poly_seq / entity_src_gen / pdbx_contact_author / pdbx_poly_seq_scheme / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / pdbx_validate_torsion / refine_ls_restr / struct_conf / struct_ref / struct_ref_seq
Item: _entity.formula_weight / _entity.pdbx_fragment ..._entity.formula_weight / _entity.pdbx_fragment / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_src_gen.pdbx_end_seq_num / _refine_ls_restr.dev_ideal / _refine_ls_restr.number / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end / _struct_ref_seq.pdbx_auth_seq_align_beg / _struct_ref_seq.pdbx_auth_seq_align_end / _struct_ref_seq.seq_align_end
Description: Model completeness / Provider: author / Type: Coordinate replacement

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sialin


Theoretical massNumber of molelcules
Total (without water)54,6841
Polymers54,6841
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Sialin / H(+)/nitrate cotransporter / H(+)/sialic acid cotransporter / AST / Membrane glycoprotein HP59 / ...H(+)/nitrate cotransporter / H(+)/sialic acid cotransporter / AST / Membrane glycoprotein HP59 / Solute carrier family 17 member 5 / Vesicular H(+)/Aspartate-glutamate cotransporter


Mass: 54684.168 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC17A5 / Production host: Escherichia coli (E. coli) / References: UniProt: Q9NRA2

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Sialin complex with Fab 8B1 / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 57.2 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 394078 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033292
ELECTRON MICROSCOPYf_angle_d0.5564507
ELECTRON MICROSCOPYf_dihedral_angle_d4.564448
ELECTRON MICROSCOPYf_chiral_restr0.042521
ELECTRON MICROSCOPYf_plane_restr0.006547

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