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- PDB-8tr9: Cryo-EM structure of transglutaminase 2 bound to GDP -

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Basic information

Entry
Database: PDB / ID: 8tr9
TitleCryo-EM structure of transglutaminase 2 bound to GDP
ComponentsProtein-glutamine gamma-glutamyltransferase 2
KeywordsTRANSFERASE / GDP / Complex / Signaling / G-protein / Cancer / cryo-EM
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) / positive regulation of neurogenesis / cellular response to cocaine / apoptotic cell clearance / positive regulation of sprouting angiogenesis / positive regulation of GTPase activity / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / extracellular matrix / positive regulation of cell adhesion / bone development / protein homooligomerization / nucleosome / peptidase activity / : / regulation of apoptotic process / phospholipase C-activating G protein-coupled receptor signaling pathway / gene expression / positive regulation of apoptotic process / focal adhesion / calcium ion binding / chromatin / GTP binding / 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
GUANOSINE-5'-DIPHOSPHATE / Protein-glutamine gamma-glutamyltransferase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsAplin, C. / Cerione, R.A.
Funding support United States, 1items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2024Provider: repository / Type: Initial release
Revision 1.1Feb 12, 2025Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Protein-glutamine gamma-glutamyltransferase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)77,8562
Polymers77,4131
Non-polymers4431
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, SAXS
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Protein-glutamine gamma-glutamyltransferase 2 / Erythrocyte transglutaminase / Heart G alpha(h) / hhG alpha(h) / Isopeptidase TGM2 / Protein G ...Erythrocyte transglutaminase / Heart G alpha(h) / hhG alpha(h) / Isopeptidase TGM2 / Protein G alpha(h) / G(h) / Protein-glutamine deamidase TGM2 / Protein-glutamine dopaminyltransferase TGM2 / Protein-glutamine histaminyltransferase TGM2 / Protein-glutamine noradrenalinyltransferase TGM2 / Protein-glutamine serotonyltransferase TGM2 / Tissue transglutaminase / tTG / tTgase / Transglutaminase C / TG(C) / TGC / TGase C / Transglutaminase H / TGase H / Transglutaminase II / TGase II / Transglutaminase-2 / TG2 / TGase-2 / hTG2


Mass: 77412.680 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGM2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P21980, protein-glutamine gamma-glutamyltransferase, Hydrolases; Acting on peptide bonds (peptidases), protein-glutamine glutaminase, Transferases; Acyltransferases; Transferring ...References: UniProt: P21980, protein-glutamine gamma-glutamyltransferase, Hydrolases; Acting on peptide bonds (peptidases), protein-glutamine glutaminase, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups
#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
Has ligand of interestY
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

ComponentName: Transglutaminase 2 bound to GDP / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 51.1 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 136297 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 99.32 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0035568
ELECTRON MICROSCOPYf_angle_d0.48367564
ELECTRON MICROSCOPYf_chiral_restr0.0418832
ELECTRON MICROSCOPYf_plane_restr0.0027985
ELECTRON MICROSCOPYf_dihedral_angle_d4.3699757

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