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- PDB-9au7: Human Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptid... -

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Basic information

Entry
Database: PDB / ID: 9au7
TitleHuman Retriever VPS35L/VPS29/VPS26C complex bound to SNX17 peptide (Composite Map)
Components
  • Sorting nexin-17
  • VPS35 endosomal protein-sorting factor-like
  • Vacuolar protein sorting-associated protein 26C
  • Vacuolar protein sorting-associated protein 29
KeywordsPROTEIN TRANSPORT / Retreiver / CCC / Endosomal recycling / Sorting Nexin
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 / retrograde transport, endosome to Golgi / cholesterol catabolic process / 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 / retrograde transport, endosome to Golgi / cholesterol catabolic process / 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 / nucleus / membrane / metal ion binding / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChen, B. / Chen, Z. / Han, Y. / Boesch, D.J. / Juneja, P. / Burstein, E. / Fung, H.Y.J.
Funding support United States, 5items
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, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: VPS35 endosomal protein-sorting factor-like
B: Vacuolar protein sorting-associated protein 29
C: Vacuolar protein sorting-associated protein 26C
D: Sorting nexin-17


Theoretical massNumber of molelcules
Total (without water)167,8404
Polymers167,8404
Non-polymers00
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 VPS35 endosomal protein-sorting factor-like / Esophageal cancer-associated protein


Mass: 109700.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VPS35L, C16orf62, 101F10.2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q7Z3J2
#2: Protein Vacuolar protein sorting-associated protein 29 / hVPS29 / PEP11 homolog / Vesicle protein sorting 29


Mass: 23038.320 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VPS29, DC15, DC7, MDS007 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UBQ0
#3: Protein Vacuolar protein sorting-associated protein 26C / Down syndrome critical region protein 3 / Down syndrome critical region protein A


Mass: 33049.344 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VPS26C, DCRA, DSCR3, DSCRA / Production host: Escherichia coli (E. coli) / References: UniProt: O14972
#4: Protein/peptide Sorting nexin-17


Mass: 2052.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15036
Has protein modificationN

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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: Trimeric complex of VPS35/VPS29/VPS26 with excess SNX17 peptide
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7
SpecimenEmbedding 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

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)
EM imaging opticsEnergyfilter slit width: 10 eV

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Processing

EM software
IDNameCategoryDetails
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fittingChimeraX was used for docking the initial model.
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassificationHeterogenous Refinement
12cryoSPARC3D reconstructionNon-uniform Refinement
13ISOLDEmodel refinementIsolde was used for initial refinement of the model into the map.
14PHENIXmodel refinementReal space refinement in PHENIX was performed.
15Cootmodel refinementCoot was used for manual modeling.
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1009886 / Details: Blob picking in cryoSPARC Live
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 227973
Details: Composite map of two locally refined maps - resolution of 3.35 and 3.75 respectively. Compositing performed in ChimeraX by vop maximum.
Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingDetails: Multimer prediction of Retreiver-SNX17 complex. / Source name: AlphaFold / Type: in silico model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038781
ELECTRON MICROSCOPYf_angle_d0.59211887
ELECTRON MICROSCOPYf_dihedral_angle_d6.7011168
ELECTRON MICROSCOPYf_chiral_restr0.0411375
ELECTRON MICROSCOPYf_plane_restr0.0061505

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