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- EMDB-37593: Vibrio vulnificus MARTX effector duet (RDTND-RID) complexed with ... -

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Entry
Database: EMDB / ID: EMD-37593
TitleVibrio vulnificus MARTX effector duet (RDTND-RID) complexed with human Rac1 Q61L and calmodulin
Map datapixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)
Sample
  • Complex: RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L
    • Complex: RDTND-RID
      • Protein or peptide: RDTND-RID
    • Complex: Calmodulin
      • Protein or peptide: Calmodulin
    • Complex: Rac1
      • Protein or peptide: Rac1
KeywordsMARTX toxin / RDTND-RID / NADase / N-fatty acyl transferase / CaM / Rac1 / TOXIN
Function / homology
Function and homology information


CoA-dependent peptidyl-lysine N6-palmitoyltransferase activity / Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases) / regulation of respiratory burst / positive regulation of ovarian follicle development / regulation of neutrophil migration / negative regulation of interleukin-23 production / Activated NTRK2 signals through CDK5 / negative regulation of fibroblast migration / ruffle assembly / localization within membrane ...CoA-dependent peptidyl-lysine N6-palmitoyltransferase activity / Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases) / regulation of respiratory burst / positive regulation of ovarian follicle development / regulation of neutrophil migration / negative regulation of interleukin-23 production / Activated NTRK2 signals through CDK5 / negative regulation of fibroblast migration / ruffle assembly / localization within membrane / kinocilium / regulation of cell adhesion involved in heart morphogenesis / NTRK2 activates RAC1 / NADPH oxidase complex / Inactivation of CDC42 and RAC1 / Rac protein signal transduction / regulation of hydrogen peroxide metabolic process / engulfment of apoptotic cell / superoxide anion generation / WNT5:FZD7-mediated leishmania damping / SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion / respiratory burst / transporter inhibitor activity / motor neuron axon guidance / ruffle organization / positive regulation of bicellular tight junction assembly / GTP-dependent protein binding / midbrain dopaminergic neuron differentiation / regulation of lamellipodium assembly / thioesterase binding / regulation of stress fiber assembly / RHO GTPases activate CIT / regulation of nitric oxide biosynthetic process / Nef and signal transduction / Activation of RAC1 / PCP/CE pathway / hepatocyte growth factor receptor signaling pathway / RHO GTPases activate KTN1 / sphingosine-1-phosphate receptor signaling pathway / forebrain development / DCC mediated attractive signaling / MET activates RAP1 and RAC1 / Sema4D mediated inhibition of cell attachment and migration / Azathioprine ADME / lamellipodium assembly / Ephrin signaling / CD28 dependent Vav1 pathway / positive regulation of neutrophil chemotaxis / Wnt signaling pathway, planar cell polarity pathway / positive regulation of ruffle assembly / regulation of receptor signaling pathway via JAK-STAT / host cell cytosol / NRAGE signals death through JNK / Rho GDP-dissociation inhibitor binding / CASP4 inflammasome assembly / negative regulation of ryanodine-sensitive calcium-release channel activity / Activation of RAC1 downstream of NMDARs / small GTPase-mediated signal transduction / negative regulation of calcium ion export across plasma membrane / presynaptic endocytosis / positive regulation of Rho protein signal transduction / pericentriolar material / establishment or maintenance of cell polarity / calcineurin-mediated signaling / semaphorin-plexin signaling pathway / RHO GTPases activate PAKs / regulation of cell communication by electrical coupling involved in cardiac conduction / adenylate cyclase binding / Sema3A PAK dependent Axon repulsion / EPH-ephrin mediated repulsion of cells / protein phosphatase activator activity / regulation of postsynapse assembly / ficolin-1-rich granule membrane / regulation of calcium-mediated signaling / positive regulation of focal adhesion assembly / RHO GTPases Activate NADPH Oxidases / anatomical structure morphogenesis / positive regulation of stress fiber assembly / RHO GTPases Activate WASPs and WAVEs / regulation of synaptic vesicle endocytosis / substrate adhesion-dependent cell spreading / detection of calcium ion / regulation of cardiac muscle contraction / positive regulation of lamellipodium assembly / positive regulation of substrate adhesion-dependent cell spreading / cell-matrix adhesion / RHO GTPases activate IQGAPs / presynaptic cytosol / GPVI-mediated activation cascade / calcium channel inhibitor activity / RHO GTPases activate PKNs / catalytic complex / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / phagocytic cup / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / actin filament polymerization / regulation of heart rate / RAC1 GTPase cycle / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / titin binding
Similarity search - Function
: / : / C-terminal repeat from RTX toxins / : / : / Pasteurella multocida toxin, C2 domain / : / : / IcsB middle domain / Mcf1 protease effector domain ...: / : / C-terminal repeat from RTX toxins / : / : / Pasteurella multocida toxin, C2 domain / : / : / IcsB middle domain / Mcf1 protease effector domain / RtxA toxin / RtxA repeat / Dermonecrotic/RTX toxin, membrane localization domain / Membrane Localization Domain / CGT/MARTX, cysteine protease (CPD) domain / CGT/MARTX, cysteine protease (CPD) domain superfamily / Peptidase C80 family / CGT/MARTX cysteine protease (CPD) domain profile. / Serralysin-like metalloprotease, C-terminal / Small GTPase Rho / Small GTPase Rho domain profile. / alpha/beta hydrolase fold / Alpha/beta hydrolase fold-1 / : / Rho (Ras homology) subfamily of Ras-like small GTPases / EF-hand domain pair / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / EF-hand, calcium binding motif / Rab subfamily of small GTPases / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / Small GTP-binding protein domain / Alpha/Beta hydrolase fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Multifunctional-autoprocessing repeats-in-toxin / Calmodulin-2 / Ras-related C3 botulinum toxin substrate 1
Similarity search - Component
Biological speciesVibrio vulnificus (bacteria) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.32 Å
AuthorsLee Y / Choi S / Jang SY / Hwang J / Kim MH
Funding support Korea, Republic Of, 2 items
OrganizationGrant numberCountry
Other governmentthe Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM1382312) Korea, Republic Of
Other governmentthe Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM2112335) Korea, Republic Of
CitationJournal: Nat Commun / Year: 2024
Title: Dissemination of pathogenic bacteria is reinforced by a MARTX toxin effector duet.
Authors: Sanghyeon Choi / Youngjin Lee / Shinhye Park / Song Yee Jang / Jongbin Park / Do Won Oh / Su-Man Kim / Tae-Hwan Kim / Ga Seul Lee / Changyi Cho / Byoung Sik Kim / Donghan Lee / Eun-Hee Kim / ...Authors: Sanghyeon Choi / Youngjin Lee / Shinhye Park / Song Yee Jang / Jongbin Park / Do Won Oh / Su-Man Kim / Tae-Hwan Kim / Ga Seul Lee / Changyi Cho / Byoung Sik Kim / Donghan Lee / Eun-Hee Kim / Hae-Kap Cheong / Jeong Hee Moon / Ji-Joon Song / Jungwon Hwang / Myung Hee Kim /
Abstract: Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly ...Multiple bacterial genera take advantage of the multifunctional autoprocessing repeats-in-toxin (MARTX) toxin to invade host cells. Secretion of the MARTX toxin by Vibrio vulnificus, a deadly opportunistic pathogen that causes primary septicemia, the precursor of sepsis, is a major driver of infection; however, the molecular mechanism via which the toxin contributes to septicemia remains unclear. Here, we report the crystal and cryo-electron microscopy (EM) structures of a toxin effector duet comprising the domain of unknown function in the first position (DUF1)/Rho inactivation domain (RID) complexed with human targets. These structures reveal how the duet is used by bacteria as a potent weapon. The data show that DUF1 acts as a RID-dependent transforming NADase domain (RDTND) that disrupts NAD homeostasis by hijacking calmodulin. The cryo-EM structure of the RDTND-RID duet complexed with calmodulin and Rac1, together with immunological analyses in vitro and in mice, provide mechanistic insight into how V. vulnificus uses the duet to suppress ROS generation by depleting NAD(P) and modifying Rac1 in a mutually-reinforcing manner that ultimately paralyzes first line immune responses, promotes dissemination of invaders, and induces sepsis. These data may allow development of tools or strategies to combat MARTX toxin-related human diseases.
History
DepositionSep 26, 2023-
Header (metadata) releaseJul 10, 2024-
Map releaseJul 10, 2024-
UpdateAug 7, 2024-
Current statusAug 7, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37593.png

Downloads & links

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Map

FileDownload / File: emd_37593.map.gz / Format: CCP4 / Size: 476.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.66 Å/pix.
x 500 pix.
= 330. Å		0.66 Å/pix.
x 500 pix.
= 330. Å		0.66 Å/pix.
x 500 pix.
= 330. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.66 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-1.0868115 - 1.77167
Average (Standard dev.)-0.00012427119 (±0.019421889)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions500500500
Spacing500500500
CellA=B=C: 330.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: pixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)

Fileemd_37593_half_map_1.map
Annotationpixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Half map: pixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)

Fileemd_37593_half_map_2.map
Annotationpixel size: 0.66extraction box size: 500 pixel (500 x 0.66 = 330 A)
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L

EntireName: RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L
Components
  • Complex: RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L
    • Complex: RDTND-RID
      • Protein or peptide: RDTND-RID
    • Complex: Calmodulin
      • Protein or peptide: Calmodulin
    • Complex: Rac1
      • Protein or peptide: Rac1

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Supramolecule #1: RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L

SupramoleculeName: RDTND-RID effector duet complexed with Ca2+CaM and Rac1Q61L
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: RDTND-RID

SupramoleculeName: RDTND-RID / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: single mutation, C2838A
Source (natural)Organism: Vibrio vulnificus (bacteria)

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Supramolecule #3: Calmodulin

SupramoleculeName: Calmodulin / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2 / Details: Sequence conflict, Q124E
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Rac1

SupramoleculeName: Rac1 / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3 / Details: single muatation, Q61L
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: RDTND-RID

MacromoleculeName: RDTND-RID / type: protein_or_peptide / ID: 1 / Details: single mutant C2838A / Enantiomer: LEVO
Source (natural)Organism: Vibrio vulnificus (bacteria)
SequenceString: MGEASHDSAE SLVAARAEKV ANLYRWLDTD NDVATDKYVP VPGFERVDVD VSDEVKQRMI QSMSGYIEHT DNQVPKDQAE ALATLFVEST LDYDWDKRVE FLTKLESYGY SFEAPHAEKS IVSFWSGKNF KQYRDILDNA QTDGKKVVYD IDVKGNAFAI DLNKHLMRWG ...String:
MGEASHDSAE SLVAARAEKV ANLYRWLDTD NDVATDKYVP VPGFERVDVD VSDEVKQRMI QSMSGYIEHT DNQVPKDQAE ALATLFVEST LDYDWDKRVE FLTKLESYGY SFEAPHAEKS IVSFWSGKNF KQYRDILDNA QTDGKKVVYD IDVKGNAFAI DLNKHLMRWG GLFLDPDNAE QNQLKSSIDA ATFSNTGFWS SVYATGAQND VYVIAEGGVR LGNYFWNVEL PALRQLQREG LVGEIRLLDK PVSEYKDLPA DQIGRRLTDA GVAVKVRFDA LSHERQAELL ADNPDGYKAD TLVELDVKLS AIDSMLRESL PFYSLRTERN LLVQEGEEGF EVRSWPGIDG KSKTILLDNP EDAAQQKSIE RFILANFDNF EQMPDELFLV DNKVLSHHDG RTRIIAQKED GAWTYNTNVE LMSVTELLDA AHVNGKVRGD SYQQVIDALT EYHASTVEHA DYELESVEKL LNLRKQIEGY VLGHPDSGRV EAMNSLLNQV NSRLEEVSVL AVSEQSIKAH DSFSRLYDQL DNANLKESKH LYLDGNGDFV TKGKGNLATI DQLGGSDAVL EKVKAAVTHE YGQVVADTIF ARLSANDLAK DGKGIDIAGL NKVHQAIEQH MSPVSATMYI WKPSDHSTLG HAALQIGQGR TQLEGQAAAD FNKQNYVSWW PLGSKSSNIR NIFNVATEDQ PDLKLRWSDF SQPAHQNDTL EHDMASEEND GFGLKDGETK LKRFIEKLNA AKGIDASYKD ASEGYASVLL GNPDMLASTG IPAHVFQPFV DQWNDTSYDM MDVANRFAEE LQKQAQASGD PALVEKRIDN VVRLFAERAL EEIEAFKASQ ADEGRVFRIN LEGLDVAAMQ AEWKRLSNDP DARYQLLTKN ASSTVAKVLK AGGADKLIGH TWRPKFGVWT PTELFNFGQA LQEAQLEIAA KKQSHQVTDV LDAL

UniProtKB: Multifunctional-autoprocessing repeats-in-toxin

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Macromolecule #2: Calmodulin

MacromoleculeName: Calmodulin / type: protein_or_peptide / ID: 2 / Details: Q124E, "sequence conflict" / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString:
GAMADQLTEE QIAEFKEAFS LFDKDGDGTI TTKELGTVMR SLGQNPTEAE LQDMINEVDA DGNGTIDFPE FLTMMARKMK DTDSEEEIRE AFRVFDKDGN GYISAAELRH VMTNLGEKLT DEEVDQMIRE ADIDGDGQVN YEEFVQMMTA K

UniProtKB: Calmodulin-2

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Macromolecule #3: Rac1

MacromoleculeName: Rac1 / type: protein_or_peptide / ID: 3 / Details: single mutation, Q61L / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
SequenceString:
GHMQAIKCVV VGDGAVGKTC LLISYTTNAF PGEYIPTVFD NYSANVMVDG KPVNLGLWDT AGLEDYDRLR PLSYPQTDVF LICFSLVSPA SFENVRAKWY PEVRHHCPNT PIILVGTKLD LRDDKDTIEK LKEKKLTPIT YPQGLAMAKE IGAVKYLECS ALTQRGLKTV FDEAIRAVL

UniProtKB: Ras-related C3 botulinum toxin substrate 1

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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

Concentration0.75 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
50.0 mMHEPESHydroxyethyl piperazine Ethane Sulfonicacid
150.0 mMNaClsodium chloride
1.0 %glycerolglycerol

Details: 50 mM HEPES-NaOH (pH 7.5), 150 mM NaCl, and 1% (v/v) glycerol
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 297 K / Instrument: FEI VITROBOT MARK IV
DetailsThis sample was monodisperse

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k 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 / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.4000000000000001 µm
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.32 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 247635
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial model
PDB IDChain

8k9z

source_name: PDB, initial_model_type: experimental model

5xn7

source_name: PDB, initial_model_type: experimental model

3th5

source_name: PDB, initial_model_type: experimental model

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