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- EMDB-63249: Cryo-EM structure of human MON1A-CCZ1-RAB7A -

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Entry
Database: EMDB / ID: EMD-63249
TitleCryo-EM structure of human MON1A-CCZ1-RAB7A
Map data
Sample
  • Complex: Cryo-EM structure of human MON1A-CCZ1-RAB7A
    • Complex: Ternary complex vacuolar fusion protein CCZ1 homolog with MON1A and RAB7A
      • Protein or peptide: Vacuolar fusion protein CCZ1 homolog B
    • Complex: Ternary complex of vacuolar fusion protein MON1 homolog A with CCZ1 and RAB7A
      • Protein or peptide: Vacuolar fusion protein MON1 homolog A
    • Complex: Ternary complex of Ras-related protein Rab-7a with Vacuolar fusion protein CCZ1 and MON1A
      • Protein or peptide: Ras-related protein Rab-7a
KeywordsComplex / GEF / RAB-GTPase / PROTEIN TRANSPORT
Function / homology
Function and homology information


Mon1-Ccz1 complex / synaptic vesicle recycling via endosome / lipophagy / positive regulation of viral process / phagosome acidification / protein to membrane docking / neurotransmitter receptor transport, postsynaptic endosome to lysosome / epidermal growth factor catabolic process / alveolar lamellar body / negative regulation of intralumenal vesicle formation ...Mon1-Ccz1 complex / synaptic vesicle recycling via endosome / lipophagy / positive regulation of viral process / phagosome acidification / protein to membrane docking / neurotransmitter receptor transport, postsynaptic endosome to lysosome / epidermal growth factor catabolic process / alveolar lamellar body / negative regulation of intralumenal vesicle formation / Suppression of autophagy / phagosome-lysosome fusion / negative regulation of exosomal secretion / establishment of vesicle localization / retromer complex binding / phagosome maturation / presynaptic endosome / protein localization to lysosome / endosome to plasma membrane protein transport / early endosome to late endosome transport / phagophore assembly site membrane / positive regulation of exosomal secretion / protein targeting to vacuole / RAB geranylgeranylation / protein targeting to lysosome / melanosome membrane / RAB GEFs exchange GTP for GDP on RABs / RHOD GTPase cycle / RHOF GTPase cycle / retrograde transport, endosome to Golgi / TBC/RABGAPs / endosome to lysosome transport / RHOJ GTPase cycle / RHOQ GTPase cycle / CDC42 GTPase cycle / autophagosome membrane / viral release from host cell / protein secretion / RHOH GTPase cycle / RHOG GTPase cycle / autophagosome assembly / RAC2 GTPase cycle / RAC3 GTPase cycle / bone resorption / intracellular transport / lipid catabolic process / vesicle-mediated transport / phagocytic vesicle / lipid droplet / RAC1 GTPase cycle / Prevention of phagosomal-lysosomal fusion / MHC class II antigen presentation / secretory granule membrane / guanyl-nucleotide exchange factor activity / small monomeric GTPase / response to bacterium / small GTPase binding / mitochondrial membrane / phagocytic vesicle membrane / endocytosis / positive regulation of protein catabolic process / GDP binding / synaptic vesicle membrane / late endosome membrane / late endosome / protein transport / G protein activity / lysosome / endosome membrane / lysosomal membrane / intracellular membrane-bounded organelle / 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 / CCZ1/INTU/HPS4, third Longin domain / Intu longin-like domain 2 / 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 / CCZ1/INTU/HPS4, third Longin domain / Intu longin-like domain 2 / 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)
Methodsingle particle reconstruction / negative staining / Resolution: 2.85 Å
AuthorsLi X / Li D / Tang D / Wang J / Qi S
Funding support China, 3 items
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, 2025-
Header (metadata) releaseDec 3, 2025-
Map releaseDec 3, 2025-
UpdateDec 3, 2025-
Current statusDec 3, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_63249.png

Downloads & links

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Map

FileDownload / File: emd_63249.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 265.216 Å		1.04 Å/pix.
x 256 pix.
= 265.216 Å		1.04 Å/pix.
x 256 pix.
= 265.216 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.036 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.348
Minimum - Maximum-4.016941 - 4.6503515
Average (Standard dev.)-0.000059662434 (±0.0911741)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 265.216 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_63249_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_63249_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of human MON1A-CCZ1-RAB7A

EntireName: Cryo-EM structure of human MON1A-CCZ1-RAB7A
Components
  • Complex: Cryo-EM structure of human MON1A-CCZ1-RAB7A
    • Complex: Ternary complex vacuolar fusion protein CCZ1 homolog with MON1A and RAB7A
      • Protein or peptide: Vacuolar fusion protein CCZ1 homolog B
    • Complex: Ternary complex of vacuolar fusion protein MON1 homolog A with CCZ1 and RAB7A
      • Protein or peptide: Vacuolar fusion protein MON1 homolog A
    • Complex: Ternary complex of Ras-related protein Rab-7a with Vacuolar fusion protein CCZ1 and MON1A
      • Protein or peptide: Ras-related protein Rab-7a

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Supramolecule #1: Cryo-EM structure of human MON1A-CCZ1-RAB7A

SupramoleculeName: Cryo-EM structure of human MON1A-CCZ1-RAB7A / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Supramolecule #2: Ternary complex vacuolar fusion protein CCZ1 homolog with MON1A a...

SupramoleculeName: Ternary complex vacuolar fusion protein CCZ1 homolog with MON1A and RAB7A
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Supramolecule #3: Ternary complex of vacuolar fusion protein MON1 homolog A with CC...

SupramoleculeName: Ternary complex of vacuolar fusion protein MON1 homolog A with CCZ1 and RAB7A
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Supramolecule #4: Ternary complex of Ras-related protein Rab-7a with Vacuolar fusio...

SupramoleculeName: Ternary complex of Ras-related protein Rab-7a with Vacuolar fusion protein CCZ1 and MON1A
type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 180 KDa

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Macromolecule #1: Vacuolar fusion protein CCZ1 homolog B

MacromoleculeName: Vacuolar fusion protein CCZ1 homolog B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.935016 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAAAAAGAGS GPWAAQEKQF PPALLSFFIY NPRFGPREGQ EENKILFYHP NEVEKNEKIR NVGLCEAIVQ FTRTFSPSKP AKSLHTQKN RQFFNEPEEN FWMVMVVRNP IIEKQSKDGK PVIEYQEEEL LDKVYSSVLR QCYSMYKLFN GTFLKAMEDG G VKLLKERL ...String:
MAAAAAGAGS GPWAAQEKQF PPALLSFFIY NPRFGPREGQ EENKILFYHP NEVEKNEKIR NVGLCEAIVQ FTRTFSPSKP AKSLHTQKN RQFFNEPEEN FWMVMVVRNP IIEKQSKDGK PVIEYQEEEL LDKVYSSVLR QCYSMYKLFN GTFLKAMEDG G VKLLKERL EKFFHRYLQT LHLQSCDLLD IFGGISFFPL DKMTYLKIQS FINRMEESLN IVKYTAFLYN DQLIWSGLEQ DD MRILYKY LTTSLFPRHI EPELAGRDSP IRAEMPGNLQ HYGRFLTGPL NLNDPDAKCR FPKIFVNTDD TYEELHLIVY KAM SAAVCF MIDASVHPTL DFCRRLDSIV GPQLTVLASD ICEQFNINKR MSGSEKEPQF KFIYFNHMNL AEKSTVHMRK TPSV SLTSV HPDLMKILGD INSDFTRVDE DEEIIVKAMS DYWVVGKKSD RRELYVILNQ KNANLIEVNE EVKKLCATQF NNIFF LD

UniProtKB: Vacuolar fusion protein CCZ1 homolog B

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Macromolecule #2: Vacuolar fusion protein MON1 homolog A

MacromoleculeName: Vacuolar fusion protein MON1 homolog A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 62.206281 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MATDMQRKRS SECLDGTLTP SDGQSMERAE SPTPGMAQGM EPGAGQEGAM FVHARSYEDL TESEDGAASG DSHKEGTRGP PPLPTDMRQ ISQDFSELST QLTGVARDLQ EEMLPGSSED WLEPPGAVGR PATEPPREGT TEGDEEDATE AWRLHQKHVF V LSEAGKPV ...String:
MATDMQRKRS SECLDGTLTP SDGQSMERAE SPTPGMAQGM EPGAGQEGAM FVHARSYEDL TESEDGAASG DSHKEGTRGP PPLPTDMRQ ISQDFSELST QLTGVARDLQ EEMLPGSSED WLEPPGAVGR PATEPPREGT TEGDEEDATE AWRLHQKHVF V LSEAGKPV YSRYGSEEAL SSTMGVMVAL VSFLEADKNA IRSIHADGYK VVFVRRSPLV LVAVARTRQS AQELAQELLY IY YQILSLL TGAQLSHIFQ QKQNYDLRRL LSGSERITDN LLQLMARDPS FLMGAARCLP LAAAVRDTVS ASLQQARARS LVF SILLAR NQLVALVRRK DQFLHPIDLH LLFNLISSSS SFREGEAWTP VCLPKFNAAG FFHAHISYLE PDTDLCLLLV STDR EDFFA VSDCRRRFQE RLRKRGAHLA LREALRTPYY SVAQVGIPDL RHFLYKSKSS GLFTSPEIEA PYTSEEEQER LLGLY QYLH SRAHNASRPL KTIYYTGPNE NLLAWVTGAF ELYMCYSPLG TKASAVSAIH KLMRWIRKEE DRLFILTPLT Y

UniProtKB: Vacuolar fusion protein MON1 homolog A

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Macromolecule #3: Ras-related protein Rab-7a

MacromoleculeName: Ras-related protein Rab-7a / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.515773 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MTSRKKVLLK VIILGDSGVG KTSLMNQYVN KKFSNQYKAT IGADFLTKEV MVDDRLVTMQ IWDTAGQERF QSLGVAFYRG ADCCVLVFD VTAPNTFKTL DSWRDEFLIQ ASPRDPENFP FVVLGIKIDL ENRQVATKRA QAWCYSKNNI PYFETSAKEA I NVEQAFQT ...String:
MTSRKKVLLK VIILGDSGVG KTSLMNQYVN KKFSNQYKAT IGADFLTKEV MVDDRLVTMQ IWDTAGQERF QSLGVAFYRG ADCCVLVFD VTAPNTFKTL DSWRDEFLIQ ASPRDPENFP FVVLGIKIDL ENRQVATKRA QAWCYSKNNI PYFETSAKEA I NVEQAFQT IARNALKQET EVELYNEFPE PIKLDKNDRA KASAESCSC

UniProtKB: Ras-related protein Rab-7a

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Experimental details

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Structure determination

Methodnegative staining
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.42 mg/mL
BufferpH: 8
StainingType: NEGATIVE / Material: uranyl acetate
GridMaterial: GOLD / Mesh: 300

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number real images: 6406 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 6406
CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionNumber classes used: 1246669 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 4554171
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final 3D classificationNumber classes: 1246669
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

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

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