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- EMDB-43872: Human Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptid... -

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Basic information

Entry
Database: EMDB / ID: EMD-43872
TitleHuman Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptide (Composite Map)
Map dataComposite of individually sharpened local refinement maps.
Sample
  • Complex: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide
    • Protein or peptide: VPS35 endosomal protein-sorting factor-like
    • Protein or peptide: Vacuolar protein sorting-associated protein 29
    • Protein or peptide: Vacuolar protein sorting-associated protein 26C
    • Protein or peptide: Sorting nexin-17
KeywordsRetreiver / CCC / Endosomal recycling / Sorting Nexin / PROTEIN TRANSPORT
Function / homology
Function and homology information


WNT ligand biogenesis and trafficking / retromer, cargo-selective complex / cardiac septum development / retromer complex / Golgi to plasma membrane transport / endocytic recycling / coronary vasculature development / cholesterol catabolic process / retrograde transport, endosome to Golgi / aorta development ...WNT ligand biogenesis and trafficking / retromer, cargo-selective complex / cardiac septum development / retromer complex / Golgi to plasma membrane transport / endocytic recycling / coronary vasculature development / cholesterol catabolic process / retrograde transport, endosome to Golgi / aorta development / endosomal transport / low-density lipoprotein particle receptor binding / regulation of endocytosis / ficolin-1-rich granule membrane / phosphatidylinositol binding / receptor-mediated endocytosis / kidney development / intracellular protein transport / late endosome / protein transport / cytoplasmic vesicle / early endosome / endosome / endosome membrane / signaling receptor binding / intracellular membrane-bounded organelle / Neutrophil degranulation / Golgi apparatus / signal transduction / protein-containing complex / metal ion binding / nucleus / membrane / plasma membrane / cytosol
Similarity search - Function
Sorting nexin-17 / SNX17, atypical FERM-like domain / Sorting nexin-17/31, FERM domain / : / : / Sorting Nexin 17 FERM C-terminal domain / Sortin nexin 17/31, FERM domain, F2 lobe / Sortin nexin 17/27/31, FERM domain, F1 lobe / VPS35 endosomal protein sorting factor-like / Vacuolar protein sorting protein 26 related ...Sorting nexin-17 / SNX17, atypical FERM-like domain / Sorting nexin-17/31, FERM domain / : / : / Sorting Nexin 17 FERM C-terminal domain / Sortin nexin 17/31, FERM domain, F2 lobe / Sortin nexin 17/27/31, FERM domain, F1 lobe / VPS35 endosomal protein sorting factor-like / Vacuolar protein sorting protein 26 related / Vacuolar protein sorting-associated protein 26 / Vacuolar protein sorting-associated protein 29 / Phosphodiesterase MJ0936/Vps29 / Calcineurin-like phosphoesterase domain, lpxH-type / Calcineurin-like phosphoesterase superfamily domain / Ras-associating (RA) domain profile. / Ras-associating (RA) domain / PhoX homologous domain, present in p47phox and p40phox. / PX domain profile. / PX domain / Phox homology / PX domain superfamily / Arrestin-like, C-terminal / Metallo-dependent phosphatase-like / PH-like domain superfamily / Immunoglobulin E-set
Similarity search - Domain/homology
Vacuolar protein sorting-associated protein 26C / Sorting nexin-17 / VPS35 endosomal protein-sorting factor-like / Vacuolar protein sorting-associated protein 29
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChen B / Chen Z / Han Y / Boesch DJ / Juneja P / Burstein E / Fung HYJ
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128786 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK107733 United States
National Science Foundation (NSF, United States)2047640 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP220582 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)U24GM129547 United States
CitationJournal: Nat Commun / Year: 2024
Title: Structural basis for Retriever-SNX17 assembly and endosomal sorting.
Authors: Amika Singla / Daniel J Boesch / Ho Yee Joyce Fung / Chigozie Ngoka / Avery S Enriquez / Ran Song / Daniel A Kramer / Yan Han / Esther Banarer / Andrew Lemoff / Puneet Juneja / Daniel D ...Authors: Amika Singla / Daniel J Boesch / Ho Yee Joyce Fung / Chigozie Ngoka / Avery S Enriquez / Ran Song / Daniel A Kramer / Yan Han / Esther Banarer / Andrew Lemoff / Puneet Juneja / Daniel D Billadeau / Xiaochen Bai / Zhe Chen / Emre E Turer / Ezra Burstein / Baoyu Chen /
Abstract: During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms ...During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we provide biochemical, structural, cellular, and proteomic analyses of the SNX17-Retriever interaction. Our data reveal that SNX17 adopts an autoinhibited conformation in the basal state, with its FERM domain sequestering its C-terminal tail. The binding of cargo proteins to the FERM domain displaces the C-terminal tail through direct competition. The released tail engages with Retriever by binding to a highly conserved interface between its VPS35L and VPS26C subunits, as revealed by cryogenic electron microscopy (cryo-EM). Disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargoes and altering the composition of the plasma membrane proteome. Intriguingly, the SNX17-binding pocket on Retriever can be utilized by other ligands containing a consensus acidic C-terminal tail motif. Together, our findings uncover a mechanism underlying endosomal trafficking of critical cargo proteins and reveal how Retriever can potentially engage with other regulatory factors or be exploited by pathogens.
History
DepositionFeb 28, 2024-
Header (metadata) releaseOct 30, 2024-
Map releaseOct 30, 2024-
UpdateDec 11, 2024-
Current statusDec 11, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43872.png

Downloads & links

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Map

FileDownload / File: emd_43872.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite of individually sharpened local refinement maps.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å		1.03 Å/pix.
x 320 pix.
= 329.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.12
Minimum - Maximum-0.0017561719 - 2.1746993
Average (Standard dev.)0.00066852925 (±0.018772377)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 329.59998 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: Composite of not sharpened local refinement maps.

Fileemd_43872_additional_1.map
AnnotationComposite of not sharpened local refinement maps.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide

EntireName: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide
Components
  • Complex: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide
    • Protein or peptide: VPS35 endosomal protein-sorting factor-like
    • Protein or peptide: Vacuolar protein sorting-associated protein 29
    • Protein or peptide: Vacuolar protein sorting-associated protein 26C
    • Protein or peptide: Sorting nexin-17

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Supramolecule #1: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide

SupramoleculeName: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: VPS35 endosomal protein-sorting factor-like

MacromoleculeName: VPS35 endosomal protein-sorting factor-like / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 109.700453 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAVFPWHSRN RNYKAEFASC RLEAVPLEFG DYHPLKPITV TESKTKKVNR KGSTSSTSSS SSSSVVDPLS SVLDGTDPLS MFAATADPA ALAAAMDSSR RKRDRDDNSV VGSDFEPWTN KRGEILARYT TTEKLSINLF MGSEKGKAGT ATLAMSEKVR T RLEELDDF ...String:
MAVFPWHSRN RNYKAEFASC RLEAVPLEFG DYHPLKPITV TESKTKKVNR KGSTSSTSSS SSSSVVDPLS SVLDGTDPLS MFAATADPA ALAAAMDSSR RKRDRDDNSV VGSDFEPWTN KRGEILARYT TTEKLSINLF MGSEKGKAGT ATLAMSEKVR T RLEELDDF EEGSQKELLN LTQQDYVNRI EELNQSLKDA WASDQKVKAL KIVIQCSKLL SDTSVIQFYP SKFVLITDIL DT FGKLVYE RIFSMCVDSR SVLPDHFSPE NANDTAKETC LNWFFKIASI RELIPRFYVE ASILKCNKFL SKTGISECLP RLT CMIRGI GDPLVSVYAR AYLCRVGMEV APHLKETLNK NFFDFLLTFK QIHGDTVQNQ LVVQGVELPS YLPLYPPAMD WIFQ CISYH APEALLTEMM ERCKKLGNNA LLLNSVMSAF RAEFIATRSM DFIGMIKECD ESGFPKHLLF RSLGLNLALA DPPES DRLQ ILNEAWKVIT KLKNPQDYIN CAEVWVEYTC KHFTKREVNT VLADVIKHMT PDRAFEDSYP QLQLIIKKVI AHFHDF SVL FSVEKFLPFL DMFQKESVRV EVCKCIMDAF IKHQQEPTKD PVILNALLHV CKTMHDSVNA LTLEDEKRML SYLINGF IK MVSFGRDFEQ QLSFYVESRS MFCNLEPVLV QLIHSVNRLA METRKVMKGN HSRKTAAFVR ACVAYCFITI PSLAGIFT R LNLYLHSGQV ALANQCLSQA DAFFKAAISL VPEVPKMINI DGKMRPSESF LLEFLCNFFS TLLIVPDHPE HGVLFLVRE LLNVIQDYTW EDNSDEKIRI YTCVLHLLSA MSQETYLYHI DKVDSNDSLY GGDSKFLAEN NKLCETVMAQ ILEHLKTLAK DEALKRQSS LGLSFFNSIL AHGDLRNNKL NQLSVNLWHL AQRHGCADTR TMVKTLEYIK KQSKQPDMTH LTELALRLPL Q TRT

UniProtKB: VPS35 endosomal protein-sorting factor-like

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Macromolecule #2: Vacuolar protein sorting-associated protein 29

MacromoleculeName: Vacuolar protein sorting-associated protein 29 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.03832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAGHRLVLVL GDLHIPHRCN SLPAKFKKLL VPGKIQHILC TGNLCTKESY DYLKTLAGDV HIVRGDFDEN LNYPEQKVVT VGQFKIGLI HGHQVIPWGD MASLALLQRQ FDVDILISGH THKFEAFEHE NKFYINPGSA TGAYNALETN IIPSFVLMDI Q ASTVVTYV ...String:
MAGHRLVLVL GDLHIPHRCN SLPAKFKKLL VPGKIQHILC TGNLCTKESY DYLKTLAGDV HIVRGDFDEN LNYPEQKVVT VGQFKIGLI HGHQVIPWGD MASLALLQRQ FDVDILISGH THKFEAFEHE NKFYINPGSA TGAYNALETN IIPSFVLMDI Q ASTVVTYV YQLIGDDVKV ERIEYKKPEN LYFQGGGSGG SHHHHHH

UniProtKB: Vacuolar protein sorting-associated protein 29

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Macromolecule #3: Vacuolar protein sorting-associated protein 26C

MacromoleculeName: Vacuolar protein sorting-associated protein 26C / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.049344 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGTALDIKIK RANKVYHAGE VLSGVVVISS KDSVQHQGVS LTMEGTVNLQ LSAKSVGVFE AFYNSVKPIQ IINSTIEMVK PGKFPSGKT EIPFEFPLHL KGNKVLYETY HGVFVNIQYT LRCDMKRSLL AKDLTKTCEF IVHSAPQKGK FTPSPVDFTI T PETLQNVK ...String:
MGTALDIKIK RANKVYHAGE VLSGVVVISS KDSVQHQGVS LTMEGTVNLQ LSAKSVGVFE AFYNSVKPIQ IINSTIEMVK PGKFPSGKT EIPFEFPLHL KGNKVLYETY HGVFVNIQYT LRCDMKRSLL AKDLTKTCEF IVHSAPQKGK FTPSPVDFTI T PETLQNVK ERALLPKFLL RGHLNSTNCV ITQPLTGELV VESSEAAIRS VELQLVRVET CGCAEGYARD ATEIQNIQIA DG DVCRGLS VPIYMVFPRL FTCPTLETTN FKVEFEVNIV VLLHPDHLIT ENFPLKLCRI

UniProtKB: Vacuolar protein sorting-associated protein 26C

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Macromolecule #4: Sorting nexin-17

MacromoleculeName: Sorting nexin-17 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.052094 KDa
SequenceString:
ASASDVHGNF AFEGIGDEDL

UniProtKB: Sorting nexin-17

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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

BufferpH: 7
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 64.0 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: 2.4 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 105000
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1009886 / Details: Blob picking in cryoSPARC Live
Startup modelType of model: INSILICO MODEL
In silico model: 559719 particles after 2D classification, further classified into 3 classes obtained using ab initio reconstruction.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Software - details: Non-uniform Refinement
Details: Composite map of two locally refined maps - resolution of 3.35 and 3.75 respectively. Compositing performed in ChimeraX by vop maximum.
Number images used: 227973
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC / Software - details: Heterogenous Refinement

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model / Details: Multimer prediction of Retreiver-SNX17 complex.
RefinementSpace: REAL
Output model

PDB-9au7:
Human Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptide (Composite Map)

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