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- EMDB-12073: Cryo-EM Structure of Human Thyroglobulin -

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Basic information

Entry
Database: EMDB / ID: EMD-12073
TitleCryo-EM Structure of Human Thyroglobulin
Map datahuman Thyroglobulin, composite map
Sample
  • Complex: human thyroglobulin
    • Protein or peptide: Thyroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


iodide transport / hormone biosynthetic process / thyroid hormone generation / regulation of myelination / thyroid gland development / hormone activity / signal transduction / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Thyroglobulin / Thyroglobulin type-1 repeat signature. / Thyroglobulin type-1 / Thyroglobulin type-1 superfamily / Thyroglobulin type-1 repeat / Thyroglobulin type-1 domain profile. / Thyroglobulin type I repeats. / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Carboxylesterase type B, conserved site ...Thyroglobulin / Thyroglobulin type-1 repeat signature. / Thyroglobulin type-1 / Thyroglobulin type-1 superfamily / Thyroglobulin type-1 repeat / Thyroglobulin type-1 domain profile. / Thyroglobulin type I repeats. / Tyrosine-protein kinase ephrin type A/B receptor-like / Tyrosine-protein kinase ephrin type A/B receptor-like / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human) / Human (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsAdaixo R / Righetto R / Steiner EM / Taylor NMI / Stahlberg H
Funding support Denmark, 2 items
OrganizationGrant numberCountry
Swiss National Science Foundation Denmark
Novo Nordisk FoundationNNF14CC0001 Denmark
CitationJournal: Nat Commun / Year: 2022
Title: Cryo-EM structure of native human thyroglobulin.
Authors: Ricardo Adaixo / Eva M Steiner / Ricardo D Righetto / Alexander Schmidt / Henning Stahlberg / Nicholas M I Taylor /
Abstract: The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as intraglandular iodine storage. Its ...The thyroglobulin (TG) protein is essential to thyroid hormone synthesis, plays a vital role in the regulation of metabolism, development and growth and serves as intraglandular iodine storage. Its architecture is conserved among vertebrates. Synthesis of triiodothyronine (T) and thyroxine (T) hormones depends on the conformation, iodination and post-translational modification of TG. Although structural information is available on recombinant and deglycosylated endogenous human thyroglobulin (hTG) from patients with goiters, the structure of native, fully glycosylated hTG remained unknown. Here, we present the cryo-electron microscopy structure of native and fully glycosylated hTG from healthy thyroid glands to 3.2 Å resolution. The structure provides detailed information on hormonogenic and glycosylation sites. We employ liquid chromatography-mass spectrometry (LC-MS) to validate these findings as well as other post-translational modifications and proteolytic cleavage sites. Our results offer insights into thyroid hormonogenesis of native hTG and provide a fundamental understanding of clinically relevant mutations.
History
DepositionDec 9, 2020-
Header (metadata) releaseDec 29, 2021-
Map releaseDec 29, 2021-
UpdateJan 26, 2022-
Current statusJan 26, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 7
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 7
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7b75
  • Surface level: 7
  • Imaged by UCSF Chimera
  • Download
Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_12073.png

Downloads & links

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Map

FileDownload / File: emd_12073.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationhuman Thyroglobulin, composite map
Voxel sizeX=Y=Z: 1.28 Å
Density
Contour LevelBy AUTHOR: 7.0 / Movie #1: 7
Minimum - Maximum-27.760906 - 55.14712
Average (Standard dev.)0.0007899169 (±1.0343481)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 409.59998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.281.281.28
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z409.600409.600409.600
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-27.76155.1470.001

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Supplemental data

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Mask #1

Fileemd_12073_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_12073_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_12073_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : human thyroglobulin

EntireName: human thyroglobulin
Components
  • Complex: human thyroglobulin
    • Protein or peptide: Thyroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: human thyroglobulin

SupramoleculeName: human thyroglobulin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: human thyroglobulin purified from thyroid gland tissue and non in vitro iodinated
Source (natural)Organism: Homo sapiens (human) / Organ: Thyroid / Tissue: Thyroid
Molecular weightTheoretical: 660 KDa

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Macromolecule #1: Thyroglobulin

MacromoleculeName: Thyroglobulin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Human (human) / Organ: Thyroid / Tissue: Thyroid
Molecular weightTheoretical: 305.069844 KDa
SequenceString: MALVLEIFTL LASICWVSAN IFEYQVDAQP LRPCELQRET AFLKQADYVP QCAEDGSFQT VQCQNDGRSC WCVGANGSEV LGSRQPGRP VACLSFCQLQ KQQILLSGYI NSTDTSYLPQ CQDSGDYAPV QCDVQQVQCW CVDAEGMEVY GTRQLGRPKR C PRSCEIRN ...String:
MALVLEIFTL LASICWVSAN IFEYQVDAQP LRPCELQRET AFLKQADYVP QCAEDGSFQT VQCQNDGRSC WCVGANGSEV LGSRQPGRP VACLSFCQLQ KQQILLSGYI NSTDTSYLPQ CQDSGDYAPV QCDVQQVQCW CVDAEGMEVY GTRQLGRPKR C PRSCEIRN RRLLHGVGDK SPPQCSAEGE FMPVQCKFVN TTDMMIFDLV HSYNRFPDAF VTFSSFQRRF PEVSGYCHCA DS QGRELAE TGLELLLDEI YDTIFAGLDL PSTFTETTLY RILQRRFLAV QSVISGRFRC PTKCEVERFT ATSFGHPYVP SCR RNGDYQ AVQCQTEGPC WCVDAQGKEM HGTRQQGEPP SCAEGQSCAS ERQQALSRLY FGTSGYFSQH DLFSSPEKRW ASPR VARFA TSCPPTIKEL FVDSGLLRPM VEGQSQQFSV SENLLKEAIR AIFPSRGLAR LALQFTTNPK RLQQNLFGGK FLVNV GQFN LSGALGTRGT FNFSQFFQQL GLASFLNGGR QEDLAKPLSV GLDSNSSTGT PEAAKKDGTM NKPTVGSFGF EINLQE NQN ALKFLASLLE LPEFLLFLQH AISVPEDVAR DLGDVMETVL SSQTCEQTPE RLFVPSCTTE GSYEDVQCFS GECWCVN SW GKELPGSRVR GGQPRCPTDC EKQRARMQSL MGSQPAGSTL FVPACTSEGH FLPVQCFNSE CYCVDAEGQA IPGTRSAI G KPKKCPTPCQ LQSEQAFLRT VQALLSNSSM LPTLSDTYIP QCSTDGQWRQ VQCNGPPEQV FELYQRWEAQ NKGQDLTPA KLLVKIMSYR EAASGNFSLF IQSLYEAGQQ DVFPVLSQYP SLQDVPLAAL EGKRPQPREN ILLEPYLFWQ ILNGQLSQYP GSYSDFSTP LAHFDLRNCW CVDEAGQELE GMRSEPSKLP TCPGSCEEAK LRVLQFIRET EEIVSASNSS RFPLGESFLV A KGIRLRNE DLGLPPLFPP REAFAEQFLR GSDYAIRLAA QSTLSFYQRR RFSPDDSAGA SALLRSGPYM PQCDAFGSWE PV QCHAGTG HCWCVDEKGG FIPGSLTARS LQIPQCPTTC EKSRTSGLLS SWKQARSQEN PSPKDLFVPA CLETGEYARL QAS GAGTWC VDPASGEELR PGSSSSAQCP SLCNVLKSGV LSRRVSPGYV PACRAEDGGF SPVQCDQAQG SCWCVMDSGE EVPG TRVTG GQPACESPRC PLPFNASEVV GGTILCETIS GPTGSAMQQC QLLCRQGSWS VFPPGPLICS LESGRWESQL PQPRA CQRP QLWQTIQTQG HFQLQLPPGK MCSADYADLL QTFQVFILDE LTARGFCQIQ VKTFGTLVSI PVCNNSSVQV GCLTRE RLG VNVTWKSRLE DIPVASLPDL HDIERALVGK DLLGRFTDLI QSGSFQLHLD SKTFPAETIR FLQGDHFGTS PRTWFGC SE GFYQVLTSEA SQDGLGCVKC PEGSYSQDEE CIPCPVGFYQ EQAGSLACVP CPVGRTTISA GAFSQTHCVT DCQRNEAG L QCDQNGQYRA SQKDRGSGKA FCVDGEGRRL PWWETEAPLE DSQCLMMQKF EKVPESKVIF DANAPVAVRS KVPDSEFPV MQCLTDCTED EACSFFTVST TEPEISCDFY AWTSDNVACM TSDQKRDALG NSKATSFGSL RCQVKVRSHG QDSPAVYLKK GQGSTTTLQ KRFEPTGFQN MLSGLYNPIV FSASGANLTD AHLFCLLACD RDLCCDGFVL TQVQGGAIIC GLLSSPSVLL C NVKDWMDP SEAWANATCP GVTYDQESHQ VILRLGDQEF IKSLTPLEGT QDTFTNFQQV YLWKDSDMGS RPESMGCRKD TV PRPASPT EAGLTTELFS PVDLNQVIVN GNQSLSSQKH WLFKHLFSAQ QANLWCLSRC VQEHSFCQLA EITESASLYF TCT LYPEAQ VCDDIMESNA QGCRLILPQM PKALFRKKVI LEDKVKNFYT RLPFQKLMGI SIRNKVPMSE KSISNGFFEC ERRC DADPC CTGFGFLNVS QLKGGEVTCL TLNSLGIQMC SEENGGAWRI LDCGSPDIEV HTYPFGWYQK PIAQNNAPSF CPLVV LPSL TEKVSLDSWQ SLALSSVVVD PSIRHFDVAH VSTAATSNFS AVRDLCLSEC SQHEACLITT LQTQPGAVRC MFYADT QSC THSLQGQNCR LLLREEATHI YRKPGISLLS YEASVPSVPI STHGRLLGRS QAIQVGTSWK QVDQFLGVPY AAPPLAE RR FQAPEPLNWT GSWDASKPRA SCWQPGTRTS TSPGVSEDCL YLNVFIPQNV APNASVLVFF HNTMDREESE GWPAIDGS F LAAVGNLIVV TASYRVGVFG FLSSGSGEVS GNWGLLDQVA ALTWVQTHIR GFGGDPRRVS LAADRGGADV ASIHLLTAR ATNSQLFRRA VLMGGSALSP AAVISHERAQ QQAIALAKEV SCPMSSSQEV VSCLRQKPAN VLNDAQTKLL AVSGPFHYWG PVIDGHFLR EPPARALKRS LWVEVDLLIG SSQDDGLINR AKAVKQFEES RGRTSSKTAF YQALQNSLGG EDSDARVEAA A TWYYSLEH STDDYASFSR ALENATRDYF IICPIIDMAS AWAKRARGNV FMYHAPENYG HGSLELLADV QFALGLPFYP AY EGQFSLE EKSLSLKIMQ YFSHFIRSGN PNYPYEFSRK VPTFATPWPD FVPRAGGENY KEFSELLPNR QGLKKADCSF WSK YISSLK TSADGAKGGQ SAESEEEELT AGSGLREDLL SLQEPGSKTY SK

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 16 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

Concentration2 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
25.0 mMC4H11NO3Tris-HCl
150.0 mMNaClSodium Chloride
1.0 xNaN3Sodium Azide

Details: 0.22 um filtered and degased
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 400 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 12.0 nm / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 80 % / Chamber temperature: 293.15 K / Instrument: LEICA EM GP
Detailsconcentrated SEC peak

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Electron microscopy

MicroscopeTFS KRIOS
TemperatureMin: 80.0 K / Max: 80.0 K
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Sampling interval: 5.0 µm / Digitization - Frames/image: 1-50 / Number grids imaged: 1 / Number real images: 8119 / Average exposure time: 10.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Calibrated magnification: 78125 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 215000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 593563
CTF correctionSoftware - Name: CTFFIND (ver. 4.1)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C2 (2 fold cyclic) / Algorithm: BACK PROJECTION / Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 37619
Initial angle assignmentType: RANDOM ASSIGNMENT / Software - Name: RELION (ver. 3)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 3)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-7b75:
Cryo-EM Structure of Human Thyroglobulin

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