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- PDB-9lol: Cryo-EM structure of human MON1A-CCZ1-RAB7A -

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Basic information

Entry
Database: PDB / ID: 9lol
TitleCryo-EM structure of human MON1A-CCZ1-RAB7A
Components
  • Ras-related protein Rab-7a
  • Vacuolar fusion protein CCZ1 homolog B
  • Vacuolar fusion protein MON1 homolog A
KeywordsPROTEIN TRANSPORT / Complex / GEF / RAB-GTPase
Function / homology
Function and homology information


Mon1-Ccz1 complex / phagosome acidification / lipophagy / protein to membrane docking / positive regulation of viral process / neurotransmitter receptor transport, postsynaptic endosome to lysosome / epidermal growth factor catabolic process / synaptic vesicle recycling via endosome / negative regulation of intralumenal vesicle formation / alveolar lamellar body ...Mon1-Ccz1 complex / phagosome acidification / lipophagy / protein to membrane docking / positive regulation of viral process / neurotransmitter receptor transport, postsynaptic endosome to lysosome / epidermal growth factor catabolic process / synaptic vesicle recycling via endosome / negative regulation of intralumenal vesicle formation / alveolar lamellar body / Suppression of autophagy / phagosome-lysosome fusion / negative regulation of exosomal secretion / establishment of vesicle localization / retromer complex binding / phagosome maturation / presynaptic endosome / endosome to plasma membrane protein transport / early endosome to late endosome transport / protein localization to lysosome / phagophore assembly site membrane / RAB geranylgeranylation / protein targeting to vacuole / positive regulation of exosomal secretion / melanosome membrane / protein targeting to lysosome / RAB GEFs exchange GTP for GDP on RABs / RHOD GTPase cycle / TBC/RABGAPs / retrograde transport, endosome to Golgi / RHOF GTPase cycle / endosome to lysosome transport / RHOJ GTPase cycle / RHOQ GTPase cycle / ciliary transition zone / CDC42 GTPase cycle / autophagosome membrane / RHOG GTPase cycle / viral release from host cell / RHOH GTPase cycle / protein secretion / RAC3 GTPase cycle / RAC2 GTPase cycle / bone resorption / autophagosome assembly / lipid catabolic process / phagocytic vesicle / vesicle-mediated transport / RAC1 GTPase cycle / MHC class II antigen presentation / lipid droplet / Prevention of phagosomal-lysosomal fusion / guanyl-nucleotide exchange factor activity / secretory granule membrane / small monomeric GTPase / response to bacterium / mitochondrial membrane / phagocytic vesicle membrane / small GTPase binding / endocytosis / positive regulation of protein catabolic process / GDP binding / late endosome / late endosome membrane / protein transport / synaptic vesicle membrane / G protein activity / lysosome / endosome membrane / lysosomal membrane / GTPase activity / Neutrophil degranulation / GTP binding / glutamatergic synapse / Golgi apparatus / mitochondrion / extracellular exosome / plasma membrane / cytosol
Similarity search - Function
Vacuolar fusion protein Ccz1 / Vacuolar fusion protein Mon1 / CCZ1/INTU, second Longin domain / Intu longin-like domain 2 / CCZ1/INTU/HPS4, third Longin domain / Intu longin-like domain 3 / CCZ1/INTU/HSP4, first Longin domain / First Longin domain of INTU, CCZ1 and HPS4 / FUZ/MON1/HPS1, third Longin domain / FUZ/MON1/HPS1, second Longin domain ...Vacuolar fusion protein Ccz1 / Vacuolar fusion protein Mon1 / CCZ1/INTU, second Longin domain / Intu longin-like domain 2 / CCZ1/INTU/HPS4, third Longin domain / Intu longin-like domain 3 / CCZ1/INTU/HSP4, first Longin domain / First Longin domain of INTU, CCZ1 and HPS4 / FUZ/MON1/HPS1, third Longin domain / FUZ/MON1/HPS1, second Longin domain / FUZ/MON1/HPS1, first Longin domain / First Longin domain of FUZ, MON1 and HPS1 / Second Longin domain of FUZ, MON1 and HPS1 / Third Longin domain of FUZ, MON1 and HPS1 / Small GTPase Rab domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Ras-related protein Rab-7a / Vacuolar fusion protein CCZ1 homolog B / Vacuolar fusion protein MON1 homolog A
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / Resolution: 2.85 Å
AuthorsLi, X. / Li, D. / Tang, D. / Wang, J. / Qi, S.
Funding support China, 3items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)32201025 China
National Science Foundation (NSF, China)32071214 China
National Science Foundation (NSF, China)32471311 China
CitationJournal: Life Metab / Year: 2025
Title: Cryo-EM structure of the human MON1A-CCZ1-RAB7A complex provides insights into nucleotide exchange mechanism.
Authors: Xinna Li / Dan Li / Dan Tang / Xiaofang Huang / Hui Bao / Jiawei Wang / Shiqian Qi /
Abstract: Autophagy is a fundamental cellular process, conserved across species from yeast to mammals, that plays a crucial role in maintaining cellular homeostasis. The functionally conserved MON1-CCZ1 (MC1) ...Autophagy is a fundamental cellular process, conserved across species from yeast to mammals, that plays a crucial role in maintaining cellular homeostasis. The functionally conserved MON1-CCZ1 (MC1) complex serves as a guanine nucleotide exchange factor (GEF) for the RAB GTPase RAB7A and is indispensable for directing RAB7A recruitment to autophagosome or lysosomal membranes. Despite its critical role, the precise molecular mechanism underlying the assembly of the human MON1A-CCZ1 (HsMC1) complex and its specific GEF activity towards RAB7A has remained unclear. In this study, we report the high-resolution cryo-electron microscopy (cryo-EM) structure of the HsMC1 GEF domain in a complex with the nucleotide-free RAB7A at 2.85 Å resolution. Our structural data demonstrate that engagement with the HsMC1 complex induces marked conformational shifts in the phosphate-binding loop (P-loop) and Switch I/II regions of RAB7A. A striking feature of this complex is the direct interaction between the P-loop of RAB7A and CCZ1, a structural detail not previously observed. Furthermore, biochemical assays targeting residues within Interface I or II of the HsMC1-RAB7A complex highlight their critical role in mediating the interaction and suggest a unique mechanism for nucleotide exchange facilitated by the HsMC1 complex. These findings provide novel molecular insights into the functional mechanisms of the HsMC1-RAB7A complex, offering a robust structural framework to inform future investigations into disease-related targets and therapeutic development.
History
DepositionJan 23, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Dec 3, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Vacuolar fusion protein CCZ1 homolog B
B: Vacuolar fusion protein MON1 homolog A
C: Ras-related protein Rab-7a


Theoretical massNumber of molelcules
Total (without water)141,6573
Polymers141,6573
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 Vacuolar fusion protein CCZ1 homolog B / Vacuolar fusion protein CCZ1 homolog-like


Mass: 55935.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCZ1B, C7orf28B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P86790
#2: Protein Vacuolar fusion protein MON1 homolog A


Mass: 62206.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MON1A, SAND1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q86VX9
#3: Protein Ras-related protein Rab-7a


Mass: 23515.773 Da / Num. of mol.: 1 / Mutation: N125I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RAB7A, RAB7 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P51149, small monomeric GTPase
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

Component
IDNameTypeEntity IDParent-IDSource
1Cryo-EM structure of human MON1A-CCZ1-RAB7ACOMPLEXall0RECOMBINANT
2Ternary complex vacuolar fusion protein CCZ1 homolog with MON1A and RAB7ACOMPLEX#11RECOMBINANT
3Ternary complex of vacuolar fusion protein MON1 homolog A with CCZ1 and RAB7ACOMPLEX#21RECOMBINANT
4Ternary complex of Ras-related protein Rab-7a with Vacuolar fusion protein CCZ1 and MON1ACOMPLEX#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.18 MDaNO
220.18 MDaNO
330.18 MDaNO
440.18 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Spodoptera frugiperda (fall armyworm)7108
22Spodoptera frugiperda (fall armyworm)7108
33Spodoptera frugiperda (fall armyworm)7108
44Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 8
SpecimenConc.: 0.42 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: NO
EM stainingType: NEGATIVE / Material: uranyl acetate
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of real images: 6406

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Processing

CTF correctionType: NONE
Particle selectionNum. of particles selected: 6406
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 4554171 / Num. of class averages: 1246669 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL

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