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- EMDB-52563: Cryo-EM structure of human sortilin ectodomain in complex with a ... -

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Basic information

Entry
Database: EMDB / ID: EMD-52563
TitleCryo-EM structure of human sortilin ectodomain in complex with a thyroglobulin C-terminal peptide
Map data
Sample
  • Complex: Human Sortilin ectodomain in complex with a thyroglobulin C-terminal peptide
    • Protein or peptide: Sortilin
    • Protein or peptide: Thyroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTrafficking / Vacuolar Protein Sorting / VPS10 / Beta propeller / Neurotensin binding receptor 3 / thyroglobulin / MEMBRANE PROTEIN
Function / homology
Function and homology information


neurotensin receptor activity, non-G protein-coupled / hormone biosynthetic process / myotube differentiation / nerve growth factor receptor activity / cerebellar climbing fiber to Purkinje cell synapse / D-glucose import across plasma membrane / maintenance of synapse structure / retromer complex binding / Golgi to lysosome transport / endosome transport via multivesicular body sorting pathway ...neurotensin receptor activity, non-G protein-coupled / hormone biosynthetic process / myotube differentiation / nerve growth factor receptor activity / cerebellar climbing fiber to Purkinje cell synapse / D-glucose import across plasma membrane / maintenance of synapse structure / retromer complex binding / Golgi to lysosome transport / endosome transport via multivesicular body sorting pathway / thyroid hormone generation / plasma membrane to endosome transport / nerve growth factor binding / vesicle organization / Golgi to endosome transport / trans-Golgi network transport vesicle / neurotrophin TRK receptor signaling pathway / clathrin-coated vesicle / Golgi cisterna membrane / thyroid gland development / extrinsic apoptotic signaling pathway via death domain receptors / endosome to lysosome transport / Golgi Associated Vesicle Biogenesis / ossification / clathrin-coated pit / neuropeptide signaling pathway / response to insulin / hormone activity / endocytosis / regulation of gene expression / protein transport / nuclear membrane / cytoplasmic vesicle / early endosome / lysosome / endosome membrane / G protein-coupled receptor signaling pathway / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / Golgi apparatus / enzyme binding / cell surface / signal transduction / : / extracellular region / membrane / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Thyroglobulin / : / VPS10 / Sortilin, C-terminal / Sortilin, N-terminal / : / Sortilin, neurotensin receptor 3, C-terminal / Sortilin, neurotensin receptor 3, / Vacuolar protein sorting 10 protein (Vps10p) domain profile. / VPS10 ...Thyroglobulin / : / VPS10 / Sortilin, C-terminal / Sortilin, N-terminal / : / Sortilin, neurotensin receptor 3, C-terminal / Sortilin, neurotensin receptor 3, / Vacuolar protein sorting 10 protein (Vps10p) domain profile. / VPS10 / 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 / Putative ephrin-receptor like / Carboxylesterase type B, conserved site / Carboxylesterases type-B signature 2. / Carboxylesterase, type B / Carboxylesterase family / Alpha/Beta hydrolase fold / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Thyroglobulin / Sortilin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsBoniardi I / Coscia F
Funding supportEuropean Union, 1 items
OrganizationGrant numberCountry
European Research Council (ERC)101041298European Union
CitationJournal: Nat Commun / Year: 2026
Title: Molecular recognition of thyroglobulin by sortilin.
Authors: Irene Boniardi / Giorgia Tanzi / Alessio Di Ianni / Andrea Graziadei / Marko Nedeljković / Camilla Stejskalova / Francesca Coscia /
Abstract: Sortilin is a ubiquitous membrane receptor mediating trafficking of protein cargoes. In the thyroid, sortilin binds thyroglobulin (TG) during its endocytosis, a key process in thyroid homeostasis. ...Sortilin is a ubiquitous membrane receptor mediating trafficking of protein cargoes. In the thyroid, sortilin binds thyroglobulin (TG) during its endocytosis, a key process in thyroid homeostasis. Although sortilin has been proposed to recognise highly iodinated TG, the molecular details of this interaction remain unknown. In this work, using an integrative structural biology approach, we reveal that sortilin binds an unstructured TG C-terminal peptide and exhibits a strong preference for the monomeric TG over the commonly known dimeric form. We find that sortilin-TG interaction is independent of the iodination state of TG and instead relies on the conversion to its monomeric state, presumably promoted by extracellular degradation. Furthermore, using AlphaPulldown and sequence analysis, we show that recognition of other reported ligands by sortilin likely relies on similar unstructured peptide motifs, which are not constrained to a single binding orientation within the receptor cavity. Overall, this study reveals the TG-sortilin binding interface and provides insights into the recognition mechanism of other cargoes by sortilin.
History
DepositionJan 15, 2025-
Header (metadata) releaseDec 17, 2025-
Map releaseDec 17, 2025-
UpdateJul 1, 2026-
Current statusJul 1, 2026Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52563.png

Downloads & links

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Map

FileDownload / File: emd_52563.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.75 Å/pix.
x 360 pix.
= 269.28 Å		0.75 Å/pix.
x 360 pix.
= 269.28 Å		0.75 Å/pix.
x 360 pix.
= 269.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.748 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00659
Minimum - Maximum-0.018272955 - 0.034194976
Average (Standard dev.)0.000024024313 (±0.0005563174)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 269.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_52563_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_52563_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Human Sortilin ectodomain in complex with a thyroglobulin C-termi...

EntireName: Human Sortilin ectodomain in complex with a thyroglobulin C-terminal peptide
Components
  • Complex: Human Sortilin ectodomain in complex with a thyroglobulin C-terminal peptide
    • Protein or peptide: Sortilin
    • Protein or peptide: Thyroglobulin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Human Sortilin ectodomain in complex with a thyroglobulin C-termi...

SupramoleculeName: Human Sortilin ectodomain in complex with a thyroglobulin C-terminal peptide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Sortilin ectodomain, mature form generated by furin proteolysis of its N-terminal propeptide in complex with a thyroglobulin C-terminal peptide
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Sortilin

MacromoleculeName: Sortilin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 82.94057 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QDRLDAPPPP AAPLPRWSGP IGVSWGLRAA AAGGAFPRGG RWRRSAPGED EECGRVRDFV AKLANNTHQH VFDDLRGSVS LSWVGDSTG VILVLTTFHV PLVIMTFGQS KLYRSEDYGK NFKDITDLIN NTFIRTEFGM AIGPENSGKV VLTAEVSGGS R GGRIFRSS ...String:
QDRLDAPPPP AAPLPRWSGP IGVSWGLRAA AAGGAFPRGG RWRRSAPGED EECGRVRDFV AKLANNTHQH VFDDLRGSVS LSWVGDSTG VILVLTTFHV PLVIMTFGQS KLYRSEDYGK NFKDITDLIN NTFIRTEFGM AIGPENSGKV VLTAEVSGGS R GGRIFRSS DFAKNFVQTD LPFHPLTQMM YSPQNSDYLL ALSTENGLWV SKNFGGKWEE IHKAVCLAKW GSDNTIFFTT YA NGSCKAD LGALELWRTS DLGKSFKTIG VKIYSFGLGG RFLFASVMAD KDTTRRIHVS TDQGDTWSMA QLPSVGQEQF YSI LAANDD MVFMHVDEPG DTGFGTIFTS DDRGIVYSKS LDRHLYTTTG GETDFTNVTS LRGVYITSVL SEDNSIQTMI TFDQ GGRWT HLRKPENSEC DATAKNKNEC SLHIHASYSI SQKLNVPMAP LSEPNAVGIV IAHGSVGDAI SVMVPDVYIS DDGGY SWTK MLEGPHYYTI LDSGGIIVAI EHSSRPINVI KFSTDEGQCW QTYTFTRDPI YFTGLASEPG ARSMNISIWG FTESFL TSQ WVSYTIDFKD ILERNCEEKD YTIWLAHSTD PEDYEDGCIL GYKEQFLRLR KSSVCQNGRD YVVTKQPSIC LCSLEDF LC DFGYYRPEND SKCVEQPELK GHDLEFCLYG REEHLTTNGY RKIPGDKCQG GVNPVREVKD LKKKCTSNFL SPEKQNSK S NSENLYFQSA GHHHHHHHHH H

UniProtKB: Sortilin

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Macromolecule #2: Thyroglobulin

MacromoleculeName: Thyroglobulin / type: protein_or_peptide / ID: 2
Details: This synthetic peptide corresponds to a thyroglobulin C-terminal peptide (residues 2749 to 2768)
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.211451 KDa
SequenceString:
SGLREDLLSL QEPGSKTYSK

UniProtKB: Thyroglobulin

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Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 1 / 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

Concentration3.5 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
150.0 mMNaClsodium chloride
0.5 %OGOctyl-beta-Glucoside
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV
Details1 mM of peptide

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number real images: 14574 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3023129
CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.1) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4po7

Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 47561
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 5.0)
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

4po7


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
SoftwareName: Coot (ver. 0.9.8.95)
Output model

PDB-9i0o:
Cryo-EM structure of human sortilin ectodomain in complex with a thyroglobulin C-terminal peptide

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