- EMDB-24963: Mouse retromer (VPS26/VPS35/VPS29) heterotrimer in the presence o... -
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Basic information
Entry
Database: EMDB / ID: EMD-24963
Title
Mouse 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 35
Protein or peptide: Vacuolar protein sorting-associated protein 26A
Protein or peptide: Vacuolar protein sorting-associated protein 29
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 / regulation of postsynapse assembly / mitochondrion-derived vesicle / negative regulation of protein localization / regulation of dendritic spine maintenance / negative regulation of protein homooligomerization / 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 / regulation of postsynapse assembly / mitochondrion-derived vesicle / negative regulation of protein localization / regulation of dendritic spine maintenance / negative regulation of protein homooligomerization / tubular endosome / mitochondrion to lysosome vesicle-mediated transport / positive regulation of Wnt protein secretion / regulation of terminal button organization / retromer, cargo-selective complex / vacuolar protein processing / 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 / retromer complex / mitochondrial fragmentation involved in apoptotic process / protein localization to endosome / dopaminergic synapse / neurotransmitter receptor transport, endosome to postsynaptic membrane / regulation of synapse maturation / voluntary musculoskeletal movement / transcytosis / endocytic recycling / retrograde transport, endosome to Golgi / positive regulation of protein localization to cell periphery / positive regulation of mitochondrial fission / lysosome organization / D1 dopamine receptor binding / intracellular protein transport / protein destabilization / modulation of chemical synaptic transmission / negative regulation of inflammatory response / positive regulation of protein catabolic process / positive regulation of canonical Wnt signaling pathway / late endosome / presynapse / postsynapse / vesicle / postsynaptic density / lysosome / early endosome / endosome membrane / endosome / neuron projection / negative regulation of gene expression / neuronal cell body / glutamatergic synapse / synapse / positive regulation of gene expression / perinuclear region of cytoplasm / mitochondrion / membrane / metal ion binding / cytoplasm / cytosol 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 species
Mus musculus (house mouse)
Method
single particle reconstruction / cryo EM / Resolution: 5.9 Å
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
United States
Citation
Journal: 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
Deposition
Sep 23, 2021
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Header (metadata) release
Dec 15, 2021
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Map release
Dec 15, 2021
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Update
Dec 15, 2021
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Current status
Dec 15, 2021
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
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