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- PDB-8t7c: Crystal structure of human phospholipase C gamma 2 -

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Basic information

Entry
Database: PDB / ID: 8t7c
TitleCrystal structure of human phospholipase C gamma 2
Components1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2
KeywordsHYDROLASE / Phospholipase C gamma 2 / autoinhibition / signaling / lipid metabolism
Function / homology
Function and homology information


inositol trisphosphate biosynthetic process / regulation of calcineurin-NFAT signaling cascade / follicular B cell differentiation / positive regulation of dendritic cell cytokine production / phosphoinositide phospholipase C / antifungal innate immune response / positive regulation of interleukin-23 production / cellular response to lectin / phosphorylation-dependent protein binding / positive regulation of cell cycle G1/S phase transition ...inositol trisphosphate biosynthetic process / regulation of calcineurin-NFAT signaling cascade / follicular B cell differentiation / positive regulation of dendritic cell cytokine production / phosphoinositide phospholipase C / antifungal innate immune response / positive regulation of interleukin-23 production / cellular response to lectin / phosphorylation-dependent protein binding / positive regulation of cell cycle G1/S phase transition / phosphatidylinositol metabolic process / Toll Like Receptor 4 (TLR4) Cascade / response to yeast / positive regulation of phagocytosis, engulfment / cell activation / positive regulation of neuroinflammatory response / Erythropoietin activates Phospholipase C gamma (PLCG) / phospholipase C activity / phosphatidylinositol-4,5-bisphosphate phospholipase C activity / phosphatidylinositol biosynthetic process / programmed cell death / macrophage activation involved in immune response / phospholipid catabolic process / cellular response to lipid / regulation of canonical NF-kappaB signal transduction / negative regulation of programmed cell death / positive regulation of macrophage cytokine production / toll-like receptor signaling pathway / phosphatidylinositol-mediated signaling / Dectin-2 family / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / intracellular vesicle / Synthesis of IP3 and IP4 in the cytosol / stimulatory C-type lectin receptor signaling pathway / positive regulation of reactive oxygen species biosynthetic process / B cell activation / positive regulation of intracellular signal transduction / regulation of lipid metabolic process / positive regulation of interleukin-10 production / positive regulation of receptor internalization / Generation of second messenger molecules / positive regulation of epithelial cell migration / positive regulation of type I interferon production / Role of phospholipids in phagocytosis / response to axon injury / GPVI-mediated activation cascade / release of sequestered calcium ion into cytosol / phosphotyrosine residue binding / positive regulation of interleukin-12 production / positive regulation of interleukin-2 production / FCERI mediated Ca+2 mobilization / positive regulation of calcium-mediated signaling / FCGR3A-mediated IL10 synthesis / cellular response to calcium ion / protein tyrosine kinase binding / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / lipopolysaccharide-mediated signaling pathway / B cell differentiation / B cell receptor signaling pathway / FCERI mediated MAPK activation / calcium-mediated signaling / platelet activation / positive regulation of interleukin-6 production / CLEC7A (Dectin-1) signaling / ruffle membrane / Wnt signaling pathway / Signaling by CSF1 (M-CSF) in myeloid cells / positive regulation of tumor necrosis factor production / DAP12 signaling / T cell receptor signaling pathway / scaffold protein binding / Potential therapeutics for SARS / positive regulation of canonical NF-kappaB signal transduction / positive regulation of MAPK cascade / intracellular signal transduction / membrane raft / positive regulation of gene expression / protein kinase binding / perinuclear region of cytoplasm / extracellular exosome / plasma membrane / cytoplasm / cytosol
Similarity search - Function
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2, SH3 domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma / PLC-gamma, C-terminal SH2 domain / PLC-gamma, N-terminal SH2 domain / : / PLCG EF-hand motif 2 / Pleckstrin homology domain / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain / Phosphatidylinositol-specific phospholipase C, Y domain ...1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2, SH3 domain / Phosphatidylinositol-4, 5-bisphosphate phosphodiesterase gamma / PLC-gamma, C-terminal SH2 domain / PLC-gamma, N-terminal SH2 domain / : / PLCG EF-hand motif 2 / Pleckstrin homology domain / Phosphoinositide phospholipase C family / Phospholipase C, phosphatidylinositol-specific, Y domain / Phosphatidylinositol-specific phospholipase C, Y domain / Phosphatidylinositol-specific phospholipase Y-box domain profile. / Phospholipase C, catalytic domain (part); domain Y / Phosphatidylinositol-specific phospholipase C, X domain / Phosphatidylinositol-specific phospholipase C, X domain / Phospholipase C, catalytic domain (part); domain X / Phosphatidylinositol-specific phospholipase X-box domain profile. / PLC-like phosphodiesterase, TIM beta/alpha-barrel domain superfamily / Protein kinase C conserved region 2 (CalB) / C2 domain / C2 domain / C2 domain profile. / C2 domain superfamily / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / EF-hand domain pair / PH-like domain superfamily
Similarity search - Domain/homology
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsChen, Y. / Choi, H. / Zhuang, N. / Hu, L. / Qian, D. / Wang, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Sci Adv / Year: 2024
Title: The crystal and cryo-EM structures of PLCγ2 reveal dynamic interdomain recognitions in autoinhibition.
Authors: Young-Cheul Shin / Ashlee Marie Plummer-Medeiros / Alison Mungenast / Hyeong-Wook Choi / Karen TenDyke / Xiaojie Zhu / Jennifer Shepard / Kristen Sanders / Ningning Zhuang / Liang Hu / ...Authors: Young-Cheul Shin / Ashlee Marie Plummer-Medeiros / Alison Mungenast / Hyeong-Wook Choi / Karen TenDyke / Xiaojie Zhu / Jennifer Shepard / Kristen Sanders / Ningning Zhuang / Liang Hu / Dongming Qian / Kangkang Song / Chen Xu / John Wang / Suresh B Poda / Maofu Liao / Yu Chen /
Abstract: Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain inhibitory region critical for its regulation, while ...Phospholipase C gamma 2 (PLCγ2) plays important roles in cell signaling downstream of various membrane receptors. PLCγ2 contains a multidomain inhibitory region critical for its regulation, while it has remained unclear how these domains contribute to PLCγ2 activity modulation. Here we determined three structures of human PLCγ2 in autoinhibited states, which reveal dynamic interactions at the autoinhibition interface, involving the conformational flexibility of the Src homology 3 (SH3) domain in the inhibitory region, and its previously unknown interaction with a carboxyl-terminal helical domain in the core region. We also determined a structure of PLCγ2 bound to the kinase domain of fibroblast growth factor receptor 1 (FGFR1), which demonstrates the recognition of FGFR1 by the nSH2 domain in the inhibitory region of PLCγ2. Our results provide structural insights into PLCγ2 regulation that will facilitate future mechanistic studies to understand the entire activation process.
History
DepositionJun 20, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 11, 2024Group: Database references / Structure summary / Category: citation / citation_author / 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 / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)136,1643
Polymers136,0611
Non-polymers1022
Water3,423190
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)78.340, 97.140, 180.920
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 / Phosphoinositide phospholipase C-gamma-2 / Phospholipase C-IV / PLC-IV / Phospholipase C-gamma-2 / PLC-gamma-2


Mass: 136061.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PLCG2 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P16885, phosphoinositide phospholipase C
#2: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 190 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.53 Å3/Da / Density % sol: 51.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / Details: 0.1 M Magnesium Formate, 15 % w/v PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL19U1 / Wavelength: 0.97853 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jun 1, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97853 Å / Relative weight: 1
ReflectionResolution: 2.55→48.62 Å / Num. obs: 45784 / % possible obs: 100 % / Redundancy: 6.6 % / CC1/2: 0.992 / Net I/σ(I): 8.7
Reflection shellResolution: 2.55→2.64 Å / Num. unique obs: 4415 / CC1/2: 0.789

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
XDSdata reduction
PHASERphasing
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6PBC

6pbc


Resolution: 2.55→48.62 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.889 / SU B: 13.062 / SU ML: 0.275 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.545 / ESU R Free: 0.322 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2816 2243 4.9 %RANDOM
Rwork0.2268 ---
obs0.2295 43414 99.67 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 158.21 Å2 / Biso mean: 56.755 Å2 / Biso min: 20.81 Å2
Baniso -1Baniso -2Baniso -3
1--2.71 Å20 Å2-0 Å2
2--0 Å20 Å2
3---2.71 Å2
Refinement stepCycle: final / Resolution: 2.55→48.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8198 0 5 190 8393
Biso mean--49.75 41.74 -
Num. residues----1001
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0138406
X-RAY DIFFRACTIONr_bond_other_d0.0030.0157905
X-RAY DIFFRACTIONr_angle_refined_deg1.2451.64811348
X-RAY DIFFRACTIONr_angle_other_deg1.0681.58218254
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9615998
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.30522.008478
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.593151522
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8521562
X-RAY DIFFRACTIONr_chiral_restr0.0450.21069
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.029389
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021995
X-RAY DIFFRACTIONr_mcbond_it2.4265.9384006
X-RAY DIFFRACTIONr_mcbond_other2.4255.9394003
X-RAY DIFFRACTIONr_mcangle_it4.1478.8984998
LS refinement shellResolution: 2.55→2.616 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.396 170 -
Rwork0.333 3168 -
all-3338 -
obs--99.88 %

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