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- EMDB-62922: Munc13-4-Rab27a complex with GppNHp -

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Basic information

Entry
Database: EMDB / ID: EMD-62922
TitleMunc13-4-Rab27a complex with GppNHp
Map data
Sample
  • Complex: Munc13-4-Rab27a complex with GppNHp
    • Complex: Munc13-4
      • Protein or peptide: Ras-related protein Rab-27A
    • Complex: Rab27a
    • Protein or peptide: Protein unc-13 homolog D
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER
KeywordsVesicle tethering / Familial hemophagocytic lymphohistiocytosis type 3 /FHL3 / Griscelli syndrome type 2 /GS2 / EXOCYTOSIS
Function / homology
Function and homology information


multivesicular body organization / cytotoxic T cell degranulation / positive regulation of constitutive secretory pathway / positive regulation of regulated secretory pathway / granuloma formation / melanosome localization / natural killer cell degranulation / exosomal secretion / regulation of mast cell degranulation / Weibel-Palade body ...multivesicular body organization / cytotoxic T cell degranulation / positive regulation of constitutive secretory pathway / positive regulation of regulated secretory pathway / granuloma formation / melanosome localization / natural killer cell degranulation / exosomal secretion / regulation of mast cell degranulation / Weibel-Palade body / exocytic vesicle / multivesicular body sorting pathway / melanocyte differentiation / myosin V binding / RAB geranylgeranylation / melanosome membrane / melanosome transport / multivesicular body membrane / RAB GEFs exchange GTP for GDP on RABs / complement-dependent cytotoxicity / germinal center formation / Insulin processing / antigen processing and presentation / synaptic vesicle transport / positive regulation of reactive oxygen species biosynthetic process / exocytosis / Regulation of MITF-M-dependent genes involved in pigmentation / protein secretion / positive regulation of exocytosis / photoreceptor outer segment / phagocytosis / positive regulation of substrate adhesion-dependent cell spreading / secretion / positive regulation of phagocytosis / secretory granule / small monomeric GTPase / recycling endosome / small GTPase binding / specific granule lumen / blood coagulation / azurophil granule lumen / GDP binding / melanosome / late endosome / G protein activity / defense response to virus / lysosome / apical plasma membrane / protein domain specific binding / intracellular membrane-bounded organelle / GTPase activity / dendrite / Neutrophil degranulation / positive regulation of gene expression / GTP binding / Golgi apparatus / extracellular exosome / extracellular region / metal ion binding / membrane / cytosol
Similarity search - Function
: / Rab27a/b / Mammalian uncoordinated homology 13, domain 2 / Munc13-homology domain 2 (MHD2) profile. / MUN domain / Munc13 homology 1 / MUN domain / Munc13-homology domain 1 (MHD1) profile. / : / Small GTPase Rab domain profile. ...: / Rab27a/b / Mammalian uncoordinated homology 13, domain 2 / Munc13-homology domain 2 (MHD2) profile. / MUN domain / Munc13 homology 1 / MUN domain / Munc13-homology domain 1 (MHD1) profile. / : / Small GTPase Rab domain profile. / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / C2 domain superfamily / 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-27A / Protein unc-13 homolog D
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.38 Å
AuthorsZheng X / Liu CQ / Wang S / Guan JL / He J / Ma C
Funding support China, 6 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32225024, 92254302 China
National Natural Science Foundation of China (NSFC)2022YFA1206001 China
National Natural Science Foundation of China (NSFC)32241021 China
National Natural Science Foundation of China (NSFC)32170189 China
National Natural Science Foundation of China (NSFC)3231163669 China
Other private2024A04J6348
CitationJournal: Nat Commun / Year: 2025
Title: Munc13-4 mediates tumor immune evasion by regulating the sorting and secretion of PD-L1 via exosomes.
Authors: Chuqi Liu / Dexiang Liu / Xiang Zheng / Jiali Guan / Xinyan Zhou / Haikun Zhang / Shen Wang / Qiubai Li / Gan Lu / Jun He / Cong Ma /
Abstract: Tumor-derived exosomes carry programmed death-ligand 1 (PD-L1), which binds programmed cell death protein 1 (PD-1) on T cells, suppressing immune responses locally and systemically. However, the ...Tumor-derived exosomes carry programmed death-ligand 1 (PD-L1), which binds programmed cell death protein 1 (PD-1) on T cells, suppressing immune responses locally and systemically. However, the mechanisms governing exosomal PD-L1 sorting and secretion remain elusive. Here, we identify Munc13-4 as a crucial regulator of this process. Deletion of Munc13-4 in breast tumors enhances T cell-mediated anti-tumor immunity, suppresses tumor growth, and improves the efficacy of immune checkpoint inhibitors. Mechanistically, Munc13-4 collaborates with hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), Rab27, and SNAREs to facilitate PD-L1 sorting and secretion via exosomes. Cryogenic electron microscopy (cryo-EM) analysis of the Munc13-4-Rab27a complex provide structural insights into exosome secretion. Importantly, PD-L1 sorting relies on a ternary complex composed of Munc13-4, PD-L1 and HRS, which is regulated by interferon gamma (IFNγ) signaling. A designed peptide that disrupts Munc13-4-PD-L1 interaction impedes PD-L1 sorting, enhances antitumor immunity, and suppresses tumor growth, highlighting the therapeutic potential of targeting this pathway.
History
DepositionJan 2, 2025-
Header (metadata) releaseOct 1, 2025-
Map releaseOct 1, 2025-
UpdateOct 29, 2025-
Current statusOct 29, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_62922.png

Downloads & links

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Map

FileDownload / File: emd_62922.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 600 pix.
= 438. Å		0.73 Å/pix.
x 600 pix.
= 438. Å		0.73 Å/pix.
x 600 pix.
= 438. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 7.3
Minimum - Maximum-62.441839999999999 - 116.427530000000004
Average (Standard dev.)-0.00011396181 (±0.9963341)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 438.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_62922_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_62922_half_map_2.map
Projections & Slices
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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Munc13-4-Rab27a complex with GppNHp

EntireName: Munc13-4-Rab27a complex with GppNHp
Components
  • Complex: Munc13-4-Rab27a complex with GppNHp
    • Complex: Munc13-4
      • Protein or peptide: Ras-related protein Rab-27A
    • Complex: Rab27a
    • Protein or peptide: Protein unc-13 homolog D
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER

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Supramolecule #1: Munc13-4-Rab27a complex with GppNHp

SupramoleculeName: Munc13-4-Rab27a complex with GppNHp / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: Munc13-4

SupramoleculeName: Munc13-4 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Rab27a

SupramoleculeName: Rab27a / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein unc-13 homolog D

MacromoleculeName: Protein unc-13 homolog D / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 126.816133 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSYYHHHHHH DYDIPTTENL YFQGAMGSMA TLLSHPQQRP PFLRQAIKIR RRRVRDLQDP PPQMAPEIQP PSHHFSPEQR ALLYEDALY TVLHRLGHPE PNHVTEASEL LRYLQEAFHV EPEEHQQTLQ RVRELEKPIF CLKATVKQAK GILGKDVSGF S DPYCLLGI ...String:
MSYYHHHHHH DYDIPTTENL YFQGAMGSMA TLLSHPQQRP PFLRQAIKIR RRRVRDLQDP PPQMAPEIQP PSHHFSPEQR ALLYEDALY TVLHRLGHPE PNHVTEASEL LRYLQEAFHV EPEEHQQTLQ RVRELEKPIF CLKATVKQAK GILGKDVSGF S DPYCLLGI EQGVGVPGGS PGSRHRQKAV VRHTIPEEET HRTQVITQTL NPVWDETFIL EFEDITNASF HLDMWDLDTV ES VRQKLGE LTDLHGLRRI FKEARKDKGQ DDFLGNVVLR LQDLRCREDQ WYPLEPRTET YPDRGQCHLQ FQLIHKRRAT SAS RSQPSY TVHLHLLQQL VSHEVTQHEA GSTSWDGSLS PQAATVLFLH ATQKDLSDFH QSMAQWLAYS RLYQSLEFPS SCLL HPITS IEYQWIQGRL KAEQQEELAA SFSSLLTYGL SLIRRFRSVF PLSVSDSPAR LQSLLRVLVQ MCKMKAFGEL CPNTA PLPQ LVTEALQTGT TEWFHLKQQH HQPMVQGIPE AGKALLGLVQ DVIGDLHQCQ RTWDKIFHNT LKIHLFSMAF RELQWL VAK RVQDHTTVVG DVVSPEMGES LFQLYISLKE LCQLRMSSSE RDGVLALDNF HRWFQPAIPS WLQKTYNEAL ARVQRAV QM DELVPLGELT KHSTSAVDLS TCFAQISHTA RQLDWPDPEE AFMITVKFVE DTCRLALVYC SLIKARAREL SSGQKDQG Q AANMLCVVVN DMEQLRLVIG KLPAQLAWEA LEQRVGAVLE QGQLQNTLHA QLQSALAGLG HEIRTGVRTL AEQLEVGIA KHIQKLVGVR ESVLPEDAIL PLMKFLEVEL CYMNTNLVQE NFSSLLTLLW THTLTVLVEA AASQRSSSLA SNRLKIALQN LEICFHAEG CGLPPKALHT ATFQALQRDL ELQAASSREL IRKYFCSRIQ QQAETTSEEL GAVTVKASYR ASEQKLRVEL L SASSLLPL DSNGSSDPFV QLTLEPRHEF PELAARETQK HKKDLHPLFD ETFEFLVPAE PCRKAGACLL LTVLDYDTLG AD DLEGEAF LPLREVPGLS GSEEPGEVPQ TRLPLTYPAP NGDPILQLLE GRKGDREAQV FVRLRRHRAK QASQHALRPA P

UniProtKB: Protein unc-13 homolog D

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Macromolecule #2: Ras-related protein Rab-27A

MacromoleculeName: Ras-related protein Rab-27A / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.520158 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLVPRGSH MASMTGGQQM GRGSMSDGDY DYLIKFLALG DSGVGKTSVL YQYTDGKFNS KFITTVGIDF REKRVVYRA SGPDGATGRG QRIHLQLWDT AGQERFRSLT TAFFRDAMGF LLLFDLTNEQ SFLNVRNWIS QLQMHAYCEN P DIVLCGNK ...String:
MGSSHHHHHH SSGLVPRGSH MASMTGGQQM GRGSMSDGDY DYLIKFLALG DSGVGKTSVL YQYTDGKFNS KFITTVGIDF REKRVVYRA SGPDGATGRG QRIHLQLWDT AGQERFRSLT TAFFRDAMGF LLLFDLTNEQ SFLNVRNWIS QLQMHAYCEN P DIVLCGNK SDLEDQRVVK EEEAIALAEK YGIPYFETSA ANGTNISQAI EMLLDLIMKR MERCVDKSWI PEGVVRSNGH AS TDQLSEE KEKGACGCLE HHHHHH

UniProtKB: Ras-related protein Rab-27A

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Macromolecule #3: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / type: ligand / ID: 3 / Number of copies: 1 / Formula: GNP
Molecular weightTheoretical: 522.196 Da
Chemical component information

ChemComp-GNP:
PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogue*YM

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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: 8.2
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK II

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.38 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 102381
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-9la9:
Munc13-4-Rab27a complex with GppNHp

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