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- EMDB-52562: Cryo-EM structure of human sortilin ectodomain -

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Basic information

Entry
Database: EMDB / ID: EMD-52562
TitleCryo-EM structure of human sortilin ectodomain
Map data
Sample
  • Complex: Sortilin ectodomain
    • Protein or peptide: Sortilin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTrafficking / Vacuolar Protein Sorting / VPS10 / Beta propeller / Neurotensin binding receptor 3 / MEMBRANE PROTEIN
Function / homology
Function and homology information


neurotensin receptor activity, non-G protein-coupled / nerve growth factor receptor activity / myotube differentiation / maintenance of synapse structure / cerebellar climbing fiber to Purkinje cell synapse / retromer complex binding / Golgi to lysosome transport / endosome transport via multivesicular body sorting pathway / plasma membrane to endosome transport / nerve growth factor binding ...neurotensin receptor activity, non-G protein-coupled / nerve growth factor receptor activity / myotube differentiation / maintenance of synapse structure / cerebellar climbing fiber to Purkinje cell synapse / retromer complex binding / Golgi to lysosome transport / endosome transport via multivesicular body sorting pathway / plasma membrane to endosome transport / nerve growth factor binding / vesicle organization / Golgi to endosome transport / trans-Golgi network transport vesicle / protein targeting to lysosome / clathrin-coated vesicle / : / Golgi cisterna membrane / negative regulation of fat cell differentiation / endosome to lysosome transport / neurotrophin TRK receptor signaling pathway / Golgi Associated Vesicle Biogenesis / extrinsic apoptotic signaling pathway via death domain receptors / clathrin-coated pit / ossification / neuropeptide signaling pathway / response to insulin / endocytosis / regulation of gene expression / cytoplasmic vesicle / nuclear membrane / early endosome / lysosome / endosome membrane / G protein-coupled receptor signaling pathway / lysosomal membrane / endoplasmic reticulum membrane / perinuclear region of cytoplasm / enzyme binding / cell surface / Golgi apparatus / membrane / plasma membrane / cytosol
Similarity search - Function
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 / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.1 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_52562.png

Downloads & links

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Map

FileDownload / File: emd_52562.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)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.748 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.716
Minimum - Maximum-2.5953555 - 3.9844053
Average (Standard dev.)0.0005133329 (±0.061058637)
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_52562_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_52562_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 : Sortilin ectodomain

EntireName: Sortilin ectodomain
Components
  • Complex: Sortilin ectodomain
    • Protein or peptide: Sortilin
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Sortilin ectodomain

SupramoleculeName: Sortilin ectodomain / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Sortilin ectodomain, mature form generated by furin proteolysis of its N-terminal propeptide. The protein is recombinantly produced in mammalian cells and purified using a C-terminal poly-his tag
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 #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / 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

Concentration2.5 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

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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: 15781 / 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: 5185162
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4po7

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 479743
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
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)
Output model

PDB-9i0n:
Cryo-EM structure of human sortilin ectodomain

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