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- EMDB-41574: Cryo-EM structure of transglutaminase 2 bound to GDP -

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Basic information

Entry
Database: EMDB / ID: EMD-41574
TitleCryo-EM structure of transglutaminase 2 bound to GDP
Map data
Sample
  • Complex: Transglutaminase 2 bound to GDP
    • Protein or peptide: Protein-glutamine gamma-glutamyltransferase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
KeywordsGDP / Complex / Signaling / G-protein / Cancer / cryo-EM / TRANSFERASE
Function / homology
Function and homology information


protein deamination / histone serotonyltransferase activity / histone dopaminyltransferase activity / peptide noradrenalinyltransferase activity / peptide histaminyltransferase activity / cellular response to serotonin / regulation of apoptotic cell clearance / protein-glutamine glutaminase activity / protein-glutamine glutaminase / protein-glutamine gamma-glutamyltransferase ...protein deamination / histone serotonyltransferase activity / histone dopaminyltransferase activity / peptide noradrenalinyltransferase activity / peptide histaminyltransferase activity / cellular response to serotonin / regulation of apoptotic cell clearance / protein-glutamine glutaminase activity / protein-glutamine glutaminase / protein-glutamine gamma-glutamyltransferase / positive regulation of mitochondrial calcium ion concentration / salivary gland cavitation / protein-glutamine gamma-glutamyltransferase activity / negative regulation of endoplasmic reticulum calcium ion concentration / dopamine secretion / peptide cross-linking / branching involved in salivary gland morphogenesis / cellular response to dopamine / positive regulation of small GTPase mediated signal transduction / Hydrolases; Acting on peptide bonds (peptidases) / cellular response to cocaine / apoptotic cell clearance / positive regulation of neurogenesis / positive regulation of sprouting angiogenesis / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / positive regulation of GTPase activity / extracellular matrix / positive regulation of cell adhesion / bone development / protein homooligomerization / nucleosome / peptidase activity / : / phospholipase C-activating G protein-coupled receptor signaling pathway / gene expression / regulation of apoptotic process / positive regulation of apoptotic process / focal adhesion / calcium ion binding / GTP binding / chromatin / perinuclear region of cytoplasm / endoplasmic reticulum / mitochondrion / proteolysis / extracellular exosome / nucleus / plasma membrane / cytosol
Similarity search - Function
Transglutaminase, N-terminal / Transglutaminase, C-terminal / Transglutaminase, active site / Protein-glutamine gamma-glutamyltransferase, animal / Transglutaminase, C-terminal domain superfamily / : / Transglutaminase family / Transglutaminase family, C-terminal ig like domain / Transglutaminases active site. / Transglutaminase-like superfamily ...Transglutaminase, N-terminal / Transglutaminase, C-terminal / Transglutaminase, active site / Protein-glutamine gamma-glutamyltransferase, animal / Transglutaminase, C-terminal domain superfamily / : / Transglutaminase family / Transglutaminase family, C-terminal ig like domain / Transglutaminases active site. / Transglutaminase-like superfamily / Transglutaminase/protease-like homologues / Transglutaminase-like / Transglutaminase-like superfamily / Papain-like cysteine peptidase superfamily / Immunoglobulin E-set / Immunoglobulin-like fold
Similarity search - Domain/homology
Protein-glutamine gamma-glutamyltransferase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsAplin C / Cerione RA
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R01CA201402-09 United States
CitationJournal: Commun Biol / Year: 2024
Title: Distinct conformational states enable transglutaminase 2 to promote cancer cell survival versus cell death.
Authors: Cody Aplin / Kara A Zielinski / Suzette Pabit / Deborah Ogunribido / William P Katt / Lois Pollack / Richard A Cerione / Shawn K Milano /
Abstract: Transglutaminase 2 (TG2) is a GTP-binding, protein-crosslinking enzyme that has been investigated as a therapeutic target for Celiac disease, neurological disorders, and aggressive cancers. TG2 has ...Transglutaminase 2 (TG2) is a GTP-binding, protein-crosslinking enzyme that has been investigated as a therapeutic target for Celiac disease, neurological disorders, and aggressive cancers. TG2 has been suggested to adopt two conformational states that regulate its functions: a GTP-bound, closed conformation, and a calcium-bound, crosslinking-active open conformation. TG2 mutants that constitutively adopt an open conformation are cytotoxic to cancer cells. Thus, small molecules that bind and stabilize the open conformation of TG2 could offer a new therapeutic strategy. Here, we investigate TG2, using static and time-resolved small-angle X-ray scattering (SAXS) and single-particle cryoelectron microscopy (cryo-EM), to determine the conformational states responsible for conferring its biological effects. We also describe a newly developed TG2 inhibitor, LM11, that potently kills glioblastoma cells and use SAXS to investigate how LM11 affects the conformational states of TG2. Using SAXS and cryo-EM, we show that guanine nucleotides bind and stabilize a monomeric closed conformation while calcium binds to an open state that can form higher order oligomers. SAXS analysis suggests how a TG2 mutant that constitutively adopts the open state binds nucleotides through an alternative mechanism to wildtype TG2. Furthermore, we use time resolved SAXS to show that LM11 increases the ability of calcium to bind and stabilize an open conformation, which is not reversible by guanine nucleotides and is cytotoxic to cancer cells. Taken together, our findings demonstrate that the conformational dynamics of TG2 are more complex than previously suggested and highlight how conformational stabilization of TG2 by LM11 maintains TG2 in a cytotoxic conformational state.
History
DepositionAug 9, 2023-
Header (metadata) releaseJul 31, 2024-
Map releaseJul 31, 2024-
UpdateFeb 12, 2025-
Current statusFeb 12, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41574.png

Downloads & links

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Map

FileDownload / File: emd_41574.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.52 Å/pix.
x 512 pix.
= 264.704 Å		0.52 Å/pix.
x 512 pix.
= 264.704 Å		0.52 Å/pix.
x 512 pix.
= 264.704 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.517 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0377
Minimum - Maximum-0.10651018 - 0.2246566
Average (Standard dev.)0.000061386134 (±0.004211101)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 264.704 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_41574_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_41574_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Transglutaminase 2 bound to GDP

EntireName: Transglutaminase 2 bound to GDP
Components
  • Complex: Transglutaminase 2 bound to GDP
    • Protein or peptide: Protein-glutamine gamma-glutamyltransferase 2
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Transglutaminase 2 bound to GDP

SupramoleculeName: Transglutaminase 2 bound to GDP / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Protein-glutamine gamma-glutamyltransferase 2

MacromoleculeName: Protein-glutamine gamma-glutamyltransferase 2 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: protein-glutamine gamma-glutamyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 77.41268 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: MAEELVLERC DLELETNGRD HHTADLCREK LVVRRGQPFW LTLHFEGRNY EASVDSLTFS VVTGPAPSQE AGTKARFPLR DAVEEGDWT ATVVDQQDCT LSLQLTTPAN APIGLYRLSL EASTGYQGSS FVLGHFILLF NAWCPADAVY LDSEEERQEY V LTQQGFIY ...String:
MAEELVLERC DLELETNGRD HHTADLCREK LVVRRGQPFW LTLHFEGRNY EASVDSLTFS VVTGPAPSQE AGTKARFPLR DAVEEGDWT ATVVDQQDCT LSLQLTTPAN APIGLYRLSL EASTGYQGSS FVLGHFILLF NAWCPADAVY LDSEEERQEY V LTQQGFIY QGSAKFIKNI PWNFGQFEDG ILDICLILLD VNPKFLKNAG RDCSRRSSPV YVGRVVSGMV NCNDDQGVLL GR WDNNYGD GVSPMSWIGS VDILRRWKNH GCQRVKYGQC WVFAAVACTV LRCLGIPTRV VTNYNSAHDQ NSNLLIEYFR NEF GEIQGD KSEMIWNFHC WVESWMTRPD LQPGYEGWQA LDPTPQEKSE GTYCCGPVPV RAIKEGDLST KYDAPFVFAE VNAD VVDWI QQDDGSVHKS INRSLIVGLK ISTKSVGRDE REDITHTYKY PEGSSEEREA FTRANHLNKL AEKEETGMAM RIRVG QSMN MGSDFDVFAH ITNNTAEEYV CRLLLCARTV SYNGILGPEC GTKYLLNLNL EPFSEKSVPL CILYEKYRDC LTESNL IKV RALLVEPVIN SYLLAERDLY LENPEIKIRI LGEPKQKRKL VAEVSLQNPL PVALEGCTFT VEGAGLTEEQ KTVEIPD PV EAGEEVKVRM DLLPLHMGLH KLVVNFESDK LKAVKGFRNV IIGPA

UniProtKB: Protein-glutamine gamma-glutamyltransferase 2

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Macromolecule #2: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*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: 7.5
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 200
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 51.1 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 136297
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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