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- EMDB-25524: Reconstruction of full-length Prex-1 (PtdIns(3,4,5)P3-dependent R... -

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Basic information

Entry
Database: EMDB / ID: EMD-25524
TitleReconstruction of full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)
Map data
Sample
  • Complex: full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)
    • Protein or peptide: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein,Endolysin chimera
Keywordsguanine nucleotide exchange factor / metastasis / plasma membrane / Rho GTPase signalling / ONCOPROTEIN
Function / homology
Function and homology information


regulation of signaling / regulation of dendrite development / neutrophil activation / regulation of actin filament polymerization / regulation of small GTPase mediated signal transduction / RHOB GTPase cycle / NRAGE signals death through JNK / superoxide metabolic process / RHOJ GTPase cycle / RHOC GTPase cycle ...regulation of signaling / regulation of dendrite development / neutrophil activation / regulation of actin filament polymerization / regulation of small GTPase mediated signal transduction / RHOB GTPase cycle / NRAGE signals death through JNK / superoxide metabolic process / RHOJ GTPase cycle / RHOC GTPase cycle / RHOQ GTPase cycle / CDC42 GTPase cycle / RHOG GTPase cycle / T cell differentiation / RHOA GTPase cycle / RAC2 GTPase cycle / RAC3 GTPase cycle / positive regulation of substrate adhesion-dependent cell spreading / viral release from host cell by cytolysis / RAC1 GTPase cycle / actin filament polymerization / GTPase activator activity / peptidoglycan catabolic process / neutrophil chemotaxis / guanyl-nucleotide exchange factor activity / dendritic shaft / phospholipid binding / G alpha (12/13) signalling events / cell wall macromolecule catabolic process / lysozyme / lysozyme activity / growth cone / host cell cytoplasm / intracellular signal transduction / positive regulation of cell migration / defense response to bacterium / G protein-coupled receptor signaling pathway / perinuclear region of cytoplasm / enzyme binding / plasma membrane / cytosol
Similarity search - Function
Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain ...Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP) / DEP domain profile. / Domain found in Dishevelled, Egl-10, and Pleckstrin / DEP domain / Guanine-nucleotide dissociation stimulator, CDC24, conserved site / Dbl homology (DH) domain signature. / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Endolysin T4 type / T4-type lysozyme / Glycoside hydrolase, family 24 / Lysozyme domain superfamily / Phage lysozyme / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PDZ domain profile. / Domain present in PSD-95, Dlg, and ZO-1/2. / PDZ domain / PDZ superfamily / Lysozyme-like domain superfamily / PH-like domain superfamily / Winged helix DNA-binding domain superfamily / Winged helix-like DNA-binding domain superfamily
Similarity search - Domain/homology
Endolysin / Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsLupton CJ / Bayly-Jones C
Funding support Australia, 2 items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia)APP1146578 Australia
National Health and Medical Research Council (NHMRC, Australia)APP1128120 Australia
CitationJournal: Nat Struct Mol Biol / Year: 2022
Title: Structure of the metastatic factor P-Rex1 reveals a two-layered autoinhibitory mechanism.
Authors: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C ...Authors: Yong-Gang Chang / Christopher J Lupton / Charles Bayly-Jones / Alastair C Keen / Laura D'Andrea / Christina M Lucato / Joel R Steele / Hari Venugopal / Ralf B Schittenhelm / James C Whisstock / Michelle L Halls / Andrew M Ellisdon /
Abstract: P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by ...P-Rex (PI(3,4,5)P-dependent Rac exchanger) guanine nucleotide exchange factors potently activate Rho GTPases. P-Rex guanine nucleotide exchange factors are autoinhibited, synergistically activated by Gβγ and PI(3,4,5)P binding and dysregulated in cancer. Here, we use X-ray crystallography, cryogenic electron microscopy and crosslinking mass spectrometry to determine the structural basis of human P-Rex1 autoinhibition. P-Rex1 has a bipartite structure of N- and C-terminal modules connected by a C-terminal four-helix bundle that binds the N-terminal Pleckstrin homology (PH) domain. In the N-terminal module, the Dbl homology (DH) domain catalytic surface is occluded by the compact arrangement of the DH-PH-DEP1 domains. Structural analysis reveals a remarkable conformational transition to release autoinhibition, requiring a 126° opening of the DH domain hinge helix. The off-axis position of Gβγ and PI(3,4,5)P binding sites further suggests a counter-rotation of the P-Rex1 halves by 90° facilitates PH domain uncoupling from the four-helix bundle, releasing the autoinhibited DH domain to drive Rho GTPase signaling.
History
DepositionNov 24, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25524.png

Downloads & links

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Map

FileDownload / File: emd_25524.map.gz / Format: CCP4 / Size: 14.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.34564 Å
Density
Contour LevelBy AUTHOR: 0.481
Minimum - Maximum-0.00093973835 - 2.5690029
Average (Standard dev.)0.015568648 (±0.092053376)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions156156156
Spacing156156156
CellA=B=C: 209.91983 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_25524_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Additional map: #1

Fileemd_25524_additional_1.map
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Half map: #2

Fileemd_25524_half_map_1.map
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Half map: #1

Fileemd_25524_half_map_2.map
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Sample components

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Entire : full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)

EntireName: full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)
Components
  • Complex: full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)
    • Protein or peptide: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein,Endolysin chimera

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Supramolecule #1: full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)

SupramoleculeName: full-length Prex-1 (PtdIns(3,4,5)P3-dependent Rac Exchanger 1)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 191 KDa

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Macromolecule #1: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger ...

MacromoleculeName: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein,Endolysin chimera
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: lysozyme
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 191.462984 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGHHHHHHHH SSGSENLYFQ GRESERQLRL RLCVLNEILG TERDYVGTLR FLQSAFLHRI RQNVADSVEK GLTEENVKVL FSNIEDILE VHKDFLAALE YCLHPEPQSQ HELGNVFLKF KDKFCVYEEY CSNHEKALRL LVELNKIPTV RAFLLSCMLL G GRKTTDIP ...String:
MGHHHHHHHH SSGSENLYFQ GRESERQLRL RLCVLNEILG TERDYVGTLR FLQSAFLHRI RQNVADSVEK GLTEENVKVL FSNIEDILE VHKDFLAALE YCLHPEPQSQ HELGNVFLKF KDKFCVYEEY CSNHEKALRL LVELNKIPTV RAFLLSCMLL G GRKTTDIP LEGYLLSPIQ RICKYPLLLK ELAKRTPGKH PDHPAVQSAL QAMKTVCSNI NETKRQMEKL EALEQLQSHI EG WEGSNLT DICTQLLLQG TLLKISAGNI QERAFFLFDN LLVYCKRKSN IFEMLRIDEG LRLKIYKDTE GYYTIGIGHL LTK SPSLNA AKSELDKAIG RNTNGVITKD EAEKLFNQDV DAAVRGILRN AKLKPVYDSL DAVRRAALIN MVFQMGETGV AGFT NSLRM LQQKRWDEAA VNLAKSRWYN QTPNRAKRVI TTFRTGTWDA YSLYIFRGRI NTEVMEVENV EDGTADYHSN GYTVT NGWK IHNTAKNKWF VCMAKTAEEK QKWLDAIIRE REQRESLKLG MERDAYVMIA EKGEKLYHMM MNKKVNLIKD RRRKLS TVP KCFLGNEFVA WLLEIGEISK TEEGVNLGQA LLENGIIHHV SDKHQFKNEQ VMYRFRYDDG TYKARSELED IMSKGVR LY CRLHSLYTPV IKDRDYHLKT YKSVLPGSKL VDWLLAQGDC QTREEAVALG VGLCNNGFMH HVLEKSEFRD ESQYFRFH A DEEMEGTSSK NKQLRNDFKL VENILAKRLL ILPQEEDYGF DIEEKNKAVV VKSVQRGSLA EVAGLQVGRK IYSINEDLV FLRPFSEVES ILNQSFCSRR PLRLLVATKA KEIIKIPDQP DTLCFQIRGA APPYVYAVGR GSEAMAAGLC AGQCILKVNG SNVMNDGAP EVLEHFQAFR SRREEALGLY QWIYHTHEDA QEARASQEAS TEDPSGEQAQ EEDQADSAFP LLSLGPRLSL C EDSPMVTL TVDNVHLEHG VVYEYVSTAG VRCHVLEKIV EPRGCFGLTA KILEAFAAND SVFVENCRRL MALSSAIVTM PH FEFRNIC DTKLESIGQR IACYQEFAAQ LKSRVSPPFK QAPLEPHPLC GLDFCPTNCH INLMEVSYPK TTPSVGRSFS IRF GRKPSL IGLDPEQGHL NPMSYTQHCI TTMAAPSWKC LPAAEGDPQG QGLHDGSFGP ASGTLGQEDR GLSFLLKQED REIQ DAYLQ LFTKLDVALK EMKQYVTQIN RLLSTITEPT SGGSCDTSDK QDKLHGCLEH LFNQVDSINA LLKGPVMSRA FEETK HFPM NHSLQEFKQK EECTIRGRSL IQISIQEDPW NLPNSIKTLV DNIQRYVEDG KNQLLLALLK CTDTELQLRR DAIFCQ ALV AAVCTFSEQL LAALGYRYNN NGEYEESSRD ASRKWLEQVA ATGVLLHCQS LLSPATVKEE RTMLEDIWVT LSELDNV TF SFKQLDENYV ANTNVFYHIE GSRQALKVIF YLDSYHFSKL PSRLEGGASL RLHTALFTKV LENVEGLPSP GSQAAEDL Q QDINAQSLEK VQQYYRKLRA FYLERSNLPT DASTTAVKID QLIRPINALD ELCRLMKSFV HPKPGAAGSV GAGLIPISS ELCYRLGACQ MVMCGTGMQR STLSVSLEQA AILARSHGLL PKCIMQATDI MRKQGPRVEI LAKNLRVKDQ MPQGAPRLYR LCQPPVDGD L

UniProtKB: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Endolysin, Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Phosphatidylinositol ...UniProtKB: Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Endolysin, Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein, Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 protein

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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

Concentration0.18 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER / Details: Ab initio
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 123896
FSC plot (resolution estimation)

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