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- PDB-6irt: human LAT1-4F2hc complex bound with BCH -

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Basic information

Entry
Database: PDB / ID: 6irt
Titlehuman LAT1-4F2hc complex bound with BCH
Components
  • 4F2 cell-surface antigen heavy chain
  • Large neutral amino acids transporter small subunit 1
KeywordsMEMBRANE PROTEIN / transporter
Function / homology
Function and homology information


L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / amino acid import across plasma membrane / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine transport ...L-tryptophan transmembrane transporter activity / alanine transport / L-tryptophan transmembrane transport / positive regulation of L-leucine import across plasma membrane / cellular response to L-arginine / amino acid import across plasma membrane / thyroid hormone transmembrane transporter activity / neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine transport / L-histidine transport / apical pole of neuron / aromatic amino acid transmembrane transporter activity / amino acid transport complex / L-amino acid transmembrane transporter activity / methionine transport / : / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / isoleucine transport / L-alanine import across plasma membrane / phenylalanine transport / valine transport / L-leucine transmembrane transporter activity / proline transport / amino acid transmembrane transport / neutral amino acid transport / positive regulation of cytokine production involved in immune response / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / amino acid transmembrane transporter activity / negative regulation of vascular associated smooth muscle cell apoptotic process / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / external side of apical plasma membrane / Tryptophan catabolism / exogenous protein binding / amino acid transport / xenobiotic transport / anchoring junction / antiporter activity / response to muscle activity / Basigin interactions / microvillus membrane / response to exogenous dsRNA / positive regulation of interleukin-17 production / tryptophan transport / transport across blood-brain barrier / positive regulation of interleukin-4 production / response to hyperoxia / cellular response to glucose starvation / positive regulation of glial cell proliferation / basal plasma membrane / negative regulation of autophagy / liver regeneration / peptide antigen binding / calcium ion transport / melanosome / positive regulation of type II interferon production / double-stranded RNA binding / virus receptor activity / basolateral plasma membrane / cellular response to lipopolysaccharide / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / apical plasma membrane / protein heterodimerization activity / lysosomal membrane / negative regulation of gene expression / intracellular membrane-bounded organelle / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol
Similarity search - Function
L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / Chem-AUU / Amino acid transporter heavy chain SLC3A2 / Large neutral amino acids transporter small subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsYan, R.H. / Zhao, X. / Lei, J.L. / Zhou, Q.
Funding support China, 6items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0500402 China
Ministry of Science and Technology (China)2016YFA0501100 China
Ministry of Science and Technology (China)2015CB910101 China
National Natural Science Foundation of China31621092 China
National Natural Science Foundation of China31630017 China
National Natural Science Foundation of China81861138009 China
CitationJournal: Nature / Year: 2019
Title: Structure of the human LAT1-4F2hc heteromeric amino acid transporter complex.
Authors: Renhong Yan / Xin Zhao / Jianlin Lei / Qiang Zhou /
Abstract: The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner. LAT1, an antiporter of the ...The L-type amino acid transporter 1 (LAT1; also known as SLC7A5) catalyses the cross-membrane flux of large neutral amino acids in a sodium- and pH-independent manner. LAT1, an antiporter of the amino acid-polyamine-organocation superfamily, also catalyses the permeation of thyroid hormones, pharmaceutical drugs, and hormone precursors such as L-3,4-dihydroxyphenylalanine across membranes. Overexpression of LAT1 has been observed in a wide range of tumour cells, and it is thus a potential target for anti-cancer drugs. LAT1 forms a heteromeric amino acid transporter complex with 4F2 cell-surface antigen heavy chain (4F2hc; also known as SLC3A2)-a type II membrane glycoprotein that is essential for the stability of LAT1 and for its localization to the plasma membrane. Despite extensive cell-based characterization of the LAT1-4F2hc complex and structural determination of its homologues in bacteria, the interactions between LAT1 and 4F2hc and the working mechanism of the complex remain largely unknown. Here we report the cryo-electron microscopy structures of human LAT1-4F2hc alone and in complex with the inhibitor 2-amino-2-norbornanecarboxylic acid at resolutions of 3.3 Å and 3.5 Å, respectively. LAT1 exhibits an inward open conformation. Besides a disulfide bond association, LAT1 also interacts extensively with 4F2hc on the extracellular side, within the membrane, and on the intracellular side. Biochemical analysis reveals that 4F2hc is essential for the transport activity of the complex. Together, our characterizations shed light on the architecture of the LAT1-4F2hc complex, and provide insights into its function and the mechanisms through which it might be associated with disease.
History
DepositionNov 14, 2018Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 27, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2019Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.0Jul 29, 2020Group: Atomic model / Data collection ...Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.auth_asym_id / _atom_site.auth_seq_id ..._atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _entity.pdbx_number_of_molecules / _entity.type / _pdbx_struct_assembly_gen.asym_id_list / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

Deposited unit
A: 4F2 cell-surface antigen heavy chain
B: Large neutral amino acids transporter small subunit 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,6699
Polymers127,4062
Non-polymers3,2637
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6940 Å2
ΔGint-38 kcal/mol
Surface area43080 Å2

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Components

#1: Protein 4F2 cell-surface antigen heavy chain / / Solute carrier family 3 (Activators of dibasic and neutral amino acid transport) / member 2 / isoform CRA_a


Mass: 70160.828 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC3A2, hCG_2016598 / Production host: Homo sapiens (human) / References: UniProt: J3KPF3
#2: Protein Large neutral amino acids transporter small subunit 1 / 4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / L-type amino acid ...4F2 light chain / 4F2LC / CD98 light chain / Integral membrane protein E16 / L-type amino acid transporter 1 / hLAT1 / Solute carrier family 7 member 5 / y+ system cationic amino acid transporter


Mass: 57244.934 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC7A5, CD98LC, LAT1, MPE16 / Production host: Homo sapiens (human) / References: UniProt: Q01650
#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#4: Chemical ChemComp-3PH / 1,2-DIACYL-GLYCEROL-3-SN-PHOSPHATE / PHOSPHATIDIC ACID / Phosphatidic acid


Mass: 704.998 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C39H77O8P
#5: Chemical ChemComp-AUU / (1S,2S,4R)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid


Mass: 155.194 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H13NO2
Sequence detailsUnexpected variation that may be derived from the cDNA library used for subcloning or PCR error

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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: human LAT1-4F2hc complex bound with BCH / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.1 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
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
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.11.1_2575: / Classification: refinement
EM software
IDNameVersionCategory
4GctfCTF correction
11RELION3final Euler assignment
13RELION33D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1247297
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 262949 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.017271
ELECTRON MICROSCOPYf_angle_d1.1579904
ELECTRON MICROSCOPYf_dihedral_angle_d8.4924249
ELECTRON MICROSCOPYf_chiral_restr0.0631154
ELECTRON MICROSCOPYf_plane_restr0.0081235

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