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- EMDB-24963: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence o... -

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Basic information

Entry
Database: EMDB / ID: EMD-24963
TitleMouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence of cyclic peptide RTL4
Map data
Sample
  • Complex: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence of cyclic peptide RTL4
    • Protein or peptide: Vacuolar protein sorting-associated protein 35Vacuole
    • Protein or peptide: Vacuolar protein sorting-associated protein 26AVacuole
    • Protein or peptide: Vacuolar protein sorting-associated protein 29Vacuole
Function / homology
Function and homology information


WNT ligand biogenesis and trafficking / positive regulation of locomotion involved in locomotory behavior / neurotransmitter receptor transport, endosome to plasma membrane / negative regulation of protein localization / regulation of postsynapse assembly / mitochondrion-derived vesicle / negative regulation of protein homooligomerization / regulation of dendritic spine maintenance / tubular endosome / mitochondrion to lysosome vesicle-mediated transport ...WNT ligand biogenesis and trafficking / positive regulation of locomotion involved in locomotory behavior / neurotransmitter receptor transport, endosome to plasma membrane / negative regulation of protein localization / regulation of postsynapse assembly / mitochondrion-derived vesicle / negative regulation of protein homooligomerization / regulation of dendritic spine maintenance / tubular endosome / mitochondrion to lysosome vesicle-mediated transport / vacuolar protein processing / positive regulation of Wnt protein secretion / regulation of terminal button organization / retromer, cargo-selective complex / vesicle-mediated transport in synapse / protein localization to organelle / negative regulation of late endosome to lysosome transport / negative regulation of lysosomal protein catabolic process / positive regulation of dopamine receptor signaling pathway / positive regulation of dopamine biosynthetic process / Golgi to vacuole transport / dopaminergic synapse / mitochondrial fragmentation involved in apoptotic process / regulation of protein metabolic process / retromer complex / neurotransmitter receptor transport, endosome to postsynaptic membrane / protein localization to endosome / regulation of synapse maturation / voluntary musculoskeletal movement / transcytosis / endocytic recycling / positive regulation of protein localization to cell periphery / retrograde transport, endosome to Golgi / regulation of mitochondrion organization / positive regulation of mitochondrial fission / lysosome organization / D1 dopamine receptor binding / intracellular protein transport / modulation of chemical synaptic transmission / protein destabilization / regulation of protein stability / negative regulation of inflammatory response / positive regulation of canonical Wnt signaling pathway / positive regulation of protein catabolic process / late endosome / presynapse / postsynapse / vesicle / postsynaptic density / lysosome / early endosome / endosome membrane / endosome / neuron projection / negative regulation of gene expression / intracellular membrane-bounded organelle / neuronal cell body / glutamatergic synapse / synapse / positive regulation of gene expression / perinuclear region of cytoplasm / mitochondrion / membrane / metal ion binding / cytosol / cytoplasm
Similarity search - Function
Vacuolar protein sorting protein 26 related / Vacuolar protein sorting-associated protein 26 / Vacuolar protein sorting-associated protein 35 / Vacuolar protein sorting-associated protein 35, C-terminal / Vacuolar protein sorting-associated protein 35 / Vacuolar protein sorting-associated protein 29 / Phosphodiesterase MJ0936/Vps29 / Calcineurin-like phosphoesterase domain, lpxH-type / Calcineurin-like phosphoesterase superfamily domain / Arrestin-like, C-terminal ...Vacuolar protein sorting protein 26 related / Vacuolar protein sorting-associated protein 26 / Vacuolar protein sorting-associated protein 35 / Vacuolar protein sorting-associated protein 35, C-terminal / Vacuolar protein sorting-associated protein 35 / Vacuolar protein sorting-associated protein 29 / Phosphodiesterase MJ0936/Vps29 / Calcineurin-like phosphoesterase domain, lpxH-type / Calcineurin-like phosphoesterase superfamily domain / Arrestin-like, C-terminal / Metallo-dependent phosphatase-like / Armadillo-type fold
Similarity search - Domain/homology
Vacuolar protein sorting-associated protein 26A / Vacuolar protein sorting-associated protein 35 / Vacuolar protein sorting-associated protein 29
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsKendall AK / Jackson LP
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Sci Adv / Year: 2021
Title: De novo macrocyclic peptides for inhibiting, stabilizing, and probing the function of the retromer endosomal trafficking complex.
Authors: Kai-En Chen / Qian Guo / Timothy A Hill / Yi Cui / Amy K Kendall / Zhe Yang / Ryan J Hall / Michael D Healy / Joanna Sacharz / Suzanne J Norwood / Sachini Fonseka / Boyang Xie / Robert C ...Authors: Kai-En Chen / Qian Guo / Timothy A Hill / Yi Cui / Amy K Kendall / Zhe Yang / Ryan J Hall / Michael D Healy / Joanna Sacharz / Suzanne J Norwood / Sachini Fonseka / Boyang Xie / Robert C Reid / Natalya Leneva / Robert G Parton / Rajesh Ghai / David A Stroud / David P Fairlie / Hiroaki Suga / Lauren P Jackson / Rohan D Teasdale / Toby Passioura / Brett M Collins /
Abstract: The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson’s disease, while viral and ...The retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signaling. Mutation of the retromer subunit Vps35 causes late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function, we have created a novel series of macrocyclic peptides that bind retromer with high affinity and specificity. Crystal structures show that most of the cyclic peptides bind to Vps29 via a Pro-Leu–containing sequence, structurally mimicking known interactors such as TBC1D5 and blocking their interaction with retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting retromer. Last, tagged peptides can be used to probe the cellular localization of retromer and its functional interactions in cells, providing novel tools for studying retromer function.
History
DepositionSep 23, 2021-
Header (metadata) releaseDec 15, 2021-
Map releaseDec 15, 2021-
UpdateDec 15, 2021-
Current statusDec 15, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0047
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by radius
  • Surface level: 0.0047
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24963.png

Downloads & links

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Map

FileDownload / File: emd_24963.map.gz / Format: CCP4 / Size: 190.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.6811 Å
Density
Contour LevelBy AUTHOR: 0.0047 / Movie #1: 0.0047
Minimum - Maximum-0.0051184893 - 0.018373754
Average (Standard dev.)4.487539e-05 (±0.0008256466)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions368368368
Spacing368368368
CellA=B=C: 250.6448 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.681100543478260.681100543478260.68110054347826
M x/y/z368368368
origin x/y/z0.0000.0000.000
length x/y/z250.645250.645250.645
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS368368368
D min/max/mean-0.0050.0180.000

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Supplemental data

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Sample components

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Entire : Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence o...

EntireName: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence of cyclic peptide RTL4
Components
  • Complex: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence of cyclic peptide RTL4
    • Protein or peptide: Vacuolar protein sorting-associated protein 35Vacuole
    • Protein or peptide: Vacuolar protein sorting-associated protein 26AVacuole
    • Protein or peptide: Vacuolar protein sorting-associated protein 29Vacuole

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Supramolecule #1: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence o...

SupramoleculeName: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence of cyclic peptide RTL4
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)

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Macromolecule #1: Vacuolar protein sorting-associated protein 35

MacromoleculeName: Vacuolar protein sorting-associated protein 35 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML GELRTSMLSP KSYYELYMA ISDELHYLEV YLTDEFAKGR KVADLYELVQ YAGNIIPRLY LLITVGVVYV K SFPQSRKD ILKDLVEMCR GVQHPLRGLF LRNYLLQCTR NILPDEGEPT ...String:
MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML GELRTSMLSP KSYYELYMA ISDELHYLEV YLTDEFAKGR KVADLYELVQ YAGNIIPRLY LLITVGVVYV K SFPQSRKD ILKDLVEMCR GVQHPLRGLF LRNYLLQCTR NILPDEGEPT DEETTGDISD SM DFVLLNF AEMNKLWVRM QHQGHSRDRE KRERERQELR ILVGTNLVRL SQLEGVNVER YKQ IVLTGI LEQVVNCRDA LAQEYLMECI IQVFPDEFHL QTLNPFLRAC AELHQNVNVK NIII ALIDR LALFAHREDG PGIPAEIKLF DIFSQQVATV IQSRQDMPSE DVVSLQVSLI NLAMK CYPD RVDYVDKVLE TTVEIFNKLN LEHIATSSAV SKELTRLLKI PVDTYNNILT VLKLKH FHP LFEYFDYESR KSMSCYVLSN VLDYNTEIVS QDQVDSIMNL VSTLIQDQPD QPVEDPD PE DFADEQSLVG RFIHLLRSDD PDQQYLILNT ARKHFGAGGN QRIRFTLPPL VFAAYQLA F RYKENSQMDD KWEKKCQKIF SFAHQTISAL IKAELAELPL RLFLQGALAA GEIGFENHE TVAYEFMSQA FSLYEDEISD SKAQLAAITL IIGTFERMKC FSEENHEPLR TQCALAASEL LEEPDQGRA VSTCAHLFWS GRNTDKNGEE LHGGKRVMEC LKKALKIANQ CMDPSLQVQL F IEILNRYI YFYEKENDAV TIQVLNQLIQ KIREDLPNLE SSEETEQINK HFHNTLEHLR SR RESPESE GPIYEGLIL

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Macromolecule #2: Vacuolar protein sorting-associated protein 26A

MacromoleculeName: Vacuolar protein sorting-associated protein 26A / type: protein_or_peptide / ID: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSFLGGFFGP ICEIDVALND GETRKMAEMK TEDGKVEKHY LFYDGESVSG KVNLAFKQPG KRLEHQGIR IEFVGQIELF NDKSNTHEFV NLVKELALPG ELTQSRSYDF EFMQVEKPYE S YIGANVRL RYFLKVTIVR RLTDLVKEYD LIVHQLATYP DVNNSIKMEV ...String:
MSFLGGFFGP ICEIDVALND GETRKMAEMK TEDGKVEKHY LFYDGESVSG KVNLAFKQPG KRLEHQGIR IEFVGQIELF NDKSNTHEFV NLVKELALPG ELTQSRSYDF EFMQVEKPYE S YIGANVRL RYFLKVTIVR RLTDLVKEYD LIVHQLATYP DVNNSIKMEV GIEDCLHIEF EY NKSKYHL KDVIVGKIYF LLVRIKIQHM ELQLIKKEIT GIGPSTTTET ETIAKYEIMD GAP VKGESI PIRLFLAGYD PTPTMRDVNK KFSVRYFLNL VLVDEEDRRY FKQQEIILWR KAPE KLRKQ RTNFHQRFES PDSQASAEQP EM

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Macromolecule #3: Vacuolar protein sorting-associated protein 29

MacromoleculeName: Vacuolar protein sorting-associated protein 29 / type: protein_or_peptide / ID: 3 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MLVLVLGDLH IPHRCNSLPA KFKKLLVPGK IQHILCTGNL CTKESYDYLK TLAGDVHIVR GDFDENLNY PEQKVVTVGQ FKIGLIHGHQ VIPWGDMASL ALLQRQFDVD ILISGHTHKF E AFEHENKF YINPGSATGA YNALET

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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: 8
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: FEI FALCON III (4k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 28083

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