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- EMDB-10141: The structure of human thyroglobulin -

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Basic information

Entry
Database: EMDB / ID: EMD-10141
TitleThe structure of human thyroglobulin
Map data
Samplehuman thyroglobulin:
Thyroglobulin / (ligand) x 2
Function / homology
Function and homology information


iodide transport / thyroid hormone metabolic process / hormone biosynthetic process / regulation of myelination / thyroid gland development / hormone activity / signal transduction / extracellular region
Thyroglobulin type-1 / Carboxylesterase, type B / Tyrosine-protein kinase ephrin type A/B receptor-like / Thyroglobulin / Carboxylesterase type B, conserved site / Alpha/Beta hydrolase fold / Thyroglobulin type-1 superfamily
Thyroglobulin
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsCoscia F / Turk D / Lowe J
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Medical Research Council (United Kingdom)U105184326 to JL United Kingdom
Wellcome Trust202754/Z/16/Z to JL United Kingdom
CitationJournal: Nature / Year: 2020
Title: The structure of human thyroglobulin.
Authors: Francesca Coscia / Ajda Taler-Verčič / Veronica T Chang / Ludwig Sinn / Francis J O'Reilly / Thierry Izoré / Miha Renko / Imre Berger / Juri Rappsilber / Dušan Turk / Jan Löwe /
Abstract: Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone synthesis from TG occurs in the ...Thyroglobulin (TG) is the protein precursor of thyroid hormones, which are essential for growth, development and the control of metabolism in vertebrates. Hormone synthesis from TG occurs in the thyroid gland via the iodination and coupling of pairs of tyrosines, and is completed by TG proteolysis. Tyrosine proximity within TG is thought to enable the coupling reaction but hormonogenic tyrosines have not been clearly identified, and the lack of a three-dimensional structure of TG has prevented mechanistic understanding. Here we present the structure of full-length human thyroglobulin at a resolution of approximately 3.5 Å, determined by cryo-electron microscopy. We identified all of the hormonogenic tyrosine pairs in the structure, and verified them using site-directed mutagenesis and in vitro hormone-production assays using human TG expressed in HEK293T cells. Our analysis revealed that the proximity, flexibility and solvent exposure of the tyrosines are the key characteristics of hormonogenic sites. We transferred the reaction sites from TG to an engineered tyrosine donor-acceptor pair in the unrelated bacterial maltose-binding protein (MBP), which yielded hormone production with an efficiency comparable to that of TG. Our study provides a framework to further understand the production and regulation of thyroid hormones.
Validation ReportPDB-ID: 6scj

SummaryFull reportAbout validation report
History
DepositionJul 24, 2019-
Header (metadata) releaseJul 31, 2019-
Map releaseFeb 12, 2020-
UpdateFeb 12, 2020-
Current statusFeb 12, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6scj
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_10141.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 400 pix.
= 417.2 Å
1.04 Å/pix.
x 400 pix.
= 417.2 Å
1.04 Å/pix.
x 400 pix.
= 417.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.043 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.09685834 - 0.15069172
Average (Standard dev.)0.00011538749 (±0.0021422328)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 417.19998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0431.0431.043
M x/y/z400400400
origin x/y/z0.0000.0000.000
length x/y/z417.200417.200417.200
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS400400400
D min/max/mean-0.0900.1960.000

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Supplemental data

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Sample components

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Entire human thyroglobulin

EntireName: human thyroglobulin / Details: dimeric / Number of components: 4

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Component #1: protein, human thyroglobulin

ProteinName: human thyroglobulin / Details: dimeric / Recombinant expression: No
MassExperimental: 660 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #2: protein, Thyroglobulin

ProteinName: Thyroglobulin / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 305.069844 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: ligand, N-ACETYL-D-GLUCOSAMINE

LigandName: N-ACETYL-D-GLUCOSAMINEN-Acetylglucosamine / Number of Copies: 34 / Recombinant expression: No
MassTheoretical: 0.221208 kDa

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Component #4: ligand, BETA-D-MANNOSE

LigandName: BETA-D-MANNOSE / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 0.180156 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 0.05 mg/mL / Buffer solution: TRIS 0.05M, 0.2M NaCl pH 8 / pH: 8
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 40 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C2 (2 fold cyclic) / Number of projections: 151601
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Output model

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