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

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Basic information

Entry
Database: PDB / ID: 9i0n
TitleCryo-EM structure of human sortilin ectodomain
ComponentsSortilin
KeywordsMEMBRANE PROTEIN / Trafficking / Vacuolar Protein Sorting / VPS10 / Beta propeller / Neurotensin binding receptor 3
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBoniardi, I. / Coscia, F.
Funding supportEuropean Union, 1items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 17, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Sortilin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)84,0114
Polymers82,9411
Non-polymers1,0703
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Sortilin / 100 kDa NT receptor / Glycoprotein 95 / Gp95 / Neurotensin receptor 3 / NT3 / NTR3


Mass: 82940.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SORT1 / Cell line (production host): Expi293-F / Production host: Homo sapiens (human) / References: UniProt: Q99523
#2: 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.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
Has protein modificationY

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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: Sortilin ectodomain / Type: COMPLEX
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
Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: Expi293-F
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
2150 mMsodium chlorideNaCl1
30.5 %Octyl-beta-GlucosideOG1
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 15781
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 20 eV

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Processing

EM software
IDNameVersionCategory
7Coot0.9model fitting
8ISOLDEmodel fitting
14PHENIX1.21.1_5286model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 5185162
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 479743 / Symmetry type: POINT
Atomic model buildingPDB-ID: 4PO7

4po7


Pdb chain-ID: A / Accession code: 4PO7 / Source name: PDB / Type: experimental model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 44.72 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00295053
ELECTRON MICROSCOPYf_angle_d0.43426850
ELECTRON MICROSCOPYf_chiral_restr0.0434760
ELECTRON MICROSCOPYf_plane_restr0.0031878
ELECTRON MICROSCOPYf_dihedral_angle_d9.75891884

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